New compounds, their preparation and use

ABSTRACT

The present invention relates to compounds of formula (I)  
                 
 
     The compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).

FIELD OF INVENTION

[0001] The present invention relates to novel compounds, pharmaceuticalcompositions containing them, methods for preparing the compounds andtheir use as medicaments. More specifically, compounds of the inventioncan be utilised in the treatment and/or prevention of conditionsmediated by nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR).

BACKGROUND OF THE INVENTION

[0002] Coronary artery disease (CAD) is the major cause of death in Type2 diabetic and metabolic syndrome patients (i.e. patients that fallwithin the ‘deadly quartet’ category of impaired glucose tolerance,insulin resistance, hypertriglyceridaemia and/or obesity).

[0003] The hypolipidaemic fibrates and antidiabetic thiazolidinedionesseparately display moderately effective triglyceride-lowering activitiesalthough they are neither potent nor efficacious enough to be a singletherapy of choice for the dyslipidaemia often observed in Type 2diabetic or metabolic syndrome patients. The thiazolidinediones alsopotently lower circulating glucose levels of Type 2 diabetic animalmodels and humans. However, the fibrate class of compounds are withoutbeneficial effects on glycaemia. Studies on the molecular actions ofthese compounds indicate that thiazolidinediones and fibrates exerttheir action by activating distinct transcription factors of theperoxisome proliferator activated receptor (PPAR) family, resulting inincreased and decreased expression of specific enzymes andapolipoproteins respectively, both key-players in regulation of plasmatriglyceride content. Fibrates, on the one hand, are PPARα activators,acting primarily in the liver. Thiazolidinediones, on the other hand,are high affinity ligands for PPARγ acting primarily on adipose tissue.

[0004] Adipose tissue plays a central role in lipid homeostasis and themaintenance of energy balance in vertebrates. Adipocytes store energy inthe form of triglycerides during periods of nutritional affluence andrelease it in the form of free fatty acids at times of nutritionaldeprivation. The development of white adipose tissue is the result of acontinuous differentiation process throughout life. Much evidence pointsto the central role of PPARγ activation in initiating and regulatingthis cell differentiation. Several highly specialised proteins areinduced during adipocyte differentiation, most of them being involved inlipid storage and metabolism. The exact link from activation of PPARγ tochanges in glucose metabolism, most notably a decrease in insulinresistance in muscle, has not yet been clarified. A possible link is viafree fatty acids such that activation of PPARγ induces LipoproteinLipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoASynthetase (ACS) in adipose tissue but not in muscle tissue. This, inturn, reduces the concentration of free fatty acids in plasmadramatically, and due to substrate competition at the cellular level,skeletal muscle and other tissues with high metabolic rates eventuallyswitch from fatty acid oxidation to glucose oxidation with decreasedinsulin resistance as a consequence.

[0005] PPARα is involved in stimulating β-oxidation of fatty acids. Inrodents, a PPARCα-mediated change in the expression of genes involved infatty acid metabolism lies at the basis of the phenomenon of peroxisomeproliferation, a pleiotropic cellular response, mainly limited to liverand kidney and which can lead to hepatocarcinogenesis in rodents. Thephenomenon of peroxisome proliferation is not seen in man. In additionto its role in peroxisome proliferation in rodents, PPARα is alsoinvolved in the control of HDL cholesterol levels in rodents and humans.This effect is, at least partially, based on a PPARα-mediatedtranscriptional regulation of the major HDL apolipoproteins, apo A-I andapo A-II. The hypotriglyceridemic action of fibrates and fatty acidsalso involves PPARα and can be summarised as follows: (I) an increasedlipolysis and clearance of remnant particles, due to changes inlipoprotein lipase and apo C-III levels, (II) a stimulation of cellularfatty acid uptake and their subsequent conversion to acyl-CoAderivatives by the induction of fatty acid binding protein and acyl-CoAsynthase, (III) an induction of fatty acid β-oxidation pathways, (IV) areduction in fatty acid and triglyceride synthesis, and finally (V) adecrease in VLDL production. Hence, both enhanced catabolism oftriglyceride-rich particles as well as reduced secretion of VLDLparticles constitutes mechanisms that contribute to the hypolipidemiceffect of fibrates.

[0006] A number of compounds have been reported to be useful in thetreatment of hyperglycemia, hyperlipidemia and hypercholesterolemia(U.S. Pat. No. 5,306,726, PCT Publications nos. W091/19702, WO 95/03038,WO 96/04260, WO 94/13650, WO 94/01420, WO 97/36579, WO 97/25042, WO95/17394, WO 99/08501, WO 99/19313 and WO 99/16758).

SUMMARY OF THE INVENTION

[0007] Glucose lowering as a single approach does not overcome themacrovascular complications associated with Type 2 diabetes andmetabolic syndrome. Novel treatments of Type 2 diabetes and metabolicsyndrome must therefore aim at lowering both the overthypertriglyceridaemia associated with these syndromes as well asalleviation of hyperglycaemia.

[0008] The clinical activity of fibrates and thiazolidinedionesindicates that research for compounds displaying combined PPARα andPPARγ activation should lead to the discovery of efficacious glucose andtriglyceride lowering drugs that have great potential in the treatmentof Type 2 diabetes and the metabolic syndrome (i.e. impaired glucosetolerance, insulin resistance, hypertriglyceridaemia and/or obesity).

DETAILED DESCRIPTION OF THE INVENTION

[0009] Accordingly, the present invention relates to compounds of thegeneral formula (I):

[0010] wherein

[0011] X is hydrogen or

[0012] X is C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, heteroaryl,aralkyl, heteroaralkyl or heterocyclyl each of which is optionallysubstituted with one or more substituents selected from halogen,perhalomethyl, hydroxy, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy,C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl,aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy,C₁₋₆-alkylthio, cyano, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,carboxy or C₁₋₆-alkylester; and

[0013] Y is hydrogen or

[0014] Y is C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, C₄ ₁₂-alkenynyl,aryl, heteroaryl, aralkyl or heteroaralkyl each of which is optionallysubstituted with one or more substituents selected from halogen,C₁₋₆-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy orC₁₋₆-alkylester; and

[0015] Z is hydrogen, halogen, hydroxy or

[0016] Z is C₁₋₆-alkyl or C₁₋₆-alkoxy each of which is optionallysubstituted with one or more substituents selected from C₁₋₆-alkoxy,halogen, hydroxy, carboxy, amino or cyano; and

[0017] Q is O, S or NR₅, wherein R₅ is hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aralkyl or heteroaralkyl andwherein R₅ is optionally substituted with one or more substituentsselected from halogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and

[0018] Ar is arylene, heteroarylene or a divalent heterocyclic groupeach of which can be optionally substituted with one or moresubstituents selected from C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of whichcan be optionally substituted with halogen, hydroxy, carboxy orC₁₋₆-alkylester; and

[0019] R₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond togetherwith R₂; and

[0020] R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together withR₂; and

[0021] R₃ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl, aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl,heterocyclyl, heteroaryl or heteroaralkyl groups optionally substitutedwith one or more substituents selected from halogen, perhalomethyl,hydroxy, cyano, carboxy or C₁₋₆-alkylester; and

[0022] R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₄₋₆-alkenynyl or aryl;

[0023] n is an integer ranging from 0 to 3; and

[0024] m is an integer ranging from 0 to 1;

[0025] or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers including a racemic mixture, orpolymorphs.

[0026] In a preferred embodiment, the present invention is concernedwith compounds of formula (I)

[0027] wherein

[0028] X is hydrogen or

[0029] X is C₁₋₁₂₋alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, heteroaryl,aralkyl, heteroaralkyl or heterocyclyl each of which is optionallysubstituted with one or more substituents selected from halogen,perhalomethyl, hydroxy, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy,C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl,aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy,C₁₋₆-alkylthio, cyano, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,carboxy or C₁₋₆-alkylester; and

[0030] Y is hydrogen or

[0031] Y is C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl,aryl, heteroaryl, aralkyl or heteroaralkyl each of which is optionallysubstituted with one or more substituents selected from halogen,C₁₋₆-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy orC₁₋₆-alkylester; and

[0032] Z is hydrogen, halogen, hydroxy or

[0033] Z is C₁₋₆-alkyl or C₁₋₆-alkoxy each of which is optionallysubstituted with one or more substituents selected from C₁₋₆-alkoxy,halogen, hydroxy, carboxy, amino or cyano; and

[0034] Q is O, S or NR₅, wherein R₅ is hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₄-alkynyl, C₄₋₆-alkenynyl, aralkyl or heteroaralkyl andwherein R₅ is optionally substituted with one or more substituentsselected from halogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and

[0035] Ar is arylene, heteroarylene or a divalent heterocyclic groupeach of which can be optionally substituted with one or moresubstituents selected from C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of whichcan be optionally substituted with halogen, hydroxy, carboxy orC₁₋₆-alkylester; and

[0036] R₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond togetherwith R₂; and

[0037] R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together withR₁; and

[0038] R₃ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl, aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl,heterocyclyl, heteroaryl or heteroaralkyl groups optionally substitutedwith one or more substituents selected from halogen, perhalomethyl,hydroxy, cyano, carboxy or C₁₋₆-alkylester; and

[0039] R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl or aryl;

[0040] n is an integer ranging from 1 to 3; and

[0041] m is 1;

[0042] or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers including a racemic mixture, orpolymorphs.

[0043] In another preferred embodiment, the present invention isconcerned with compounds of formula I

[0044] wherein

[0045] X is hydrogen, C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl or heterocyclyl optionallysubstituted with one or more substituents selected from halogen,perhalomethyl, hydroxy, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy,C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl,aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy,C₁₋₆-alkylthio, cyano, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,carboxy or C₁₋₆-alkylester; and

[0046] Y is hydrogen, C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl,C₄₋₁₂-alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionallysubstituted with one or more substituents selected from halogen,C₁₋₆-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy orC₁₋₆-alkylester; and

[0047] Z is hydrogen, halogen, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxyoptionally substituted with one or more substituents selected fromC₁₋₆-alkoxy, halogen, hydroxy, carboxy, amino or cyano; and

[0048] Q is O, S or NR₅, wherein R₅ is hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aralkyl or heteroaralkyl andwherein R₅ is optionally substituted with one or more substituentsselected from halogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and

[0049] Ar is arylene, heteroarylene or a divalent heterocyclic groupeach of which can be optionally substituted with one or moresubstituents selected from C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of whichcan be optionally substituted with halogen, hydroxy, carboxy orC₁₋₆-alkylester; and

[0050] R₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond togetherwith R₂; and

[0051] R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together withR₁; and

[0052] R₃ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl, aryl, aralkyl, C₁-alkoxyC₁₋₆-alkyl, acyl, heterocyclyl,heteroaryl or heteroaralkyl groups optionally substituted with one ormore substituents selected from halogen, perhalomethyl, hydroxy, cyano,carboxy or C₁₋₆-alkylester; and

[0053] R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl or aryl;

[0054] n is an integer ranging from 0 to 3; and

[0055] m is an integer ranging from 0 to 1;

[0056] or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers including a racemic mixture, orpolymorphs.

[0057] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein X is aryl, heteroaryl orheterocyclyl optionally substituted with one or more substituentsselected from halogen, perhalomethyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl,aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl,heteroaryloxy or heteroaralkoxy.

[0058] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein X is aryl, heteroaryl orheterocyclyl each of which is optionally substituted with one or moresubstituents selected from halogen, perhalomethyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl,heteroaralkyl, heteroaryloxy or heteroaralkoxy.

[0059] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein X is aryl optionallysubstituted with one or more substituents selected from halogen,perhalomethyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio,aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy orheteroaralkoxy.

[0060] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein X is phenyl or naphthyleach of which is optionally substituted with one or more substituentsselected from halogen or perhalomethyl.

[0061] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein X is phenyl optionallysubstituted with one or more substituents selected from halogen.

[0062] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein X is phenyl.

[0063] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein X is heteroaryl optionallysubstituted with one or more substituents selected from halogen,perhalomethyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio,aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy orheteroaralkoxy.

[0064] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein X is heterocyclyloptionally substituted with one or more substituents selected fromhalogen, perhalomethyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy,arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy orheteroaralkoxy.

[0065] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein Y is hydrogen, C₁₋₁₂-alkylor aryl.

[0066] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein Y is hydrogen or methyl.

[0067] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein Y is hydrogen.

[0068] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein Z is hydrogen orC₁₋₆-alkoxy.

[0069] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein Z is hydrogen.

[0070] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein Q is O.

[0071] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein Ar is arylene optionallysubstituted with one or more substituents selected from C₁₋₆-alkyl orC₁₋₆-alkoxy each of which can be optionally substituted with carboxy.

[0072] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein Ar is phenylene.

[0073] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein R₁ is hydrogen or R₁ formsa bond together with R₂.

[0074] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein R₁ is hydrogen.

[0075] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein R₂ is hydrogen or R₂ formsa bond together with R₁.

[0076] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein R₂ is hydrogen.

[0077] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein R₃ is C₁₋₆-alkyl.

[0078] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein R₃ is C₁₋₂-alkyl.

[0079] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein R₄ is hydrogen.

[0080] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein n is 1.

[0081] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein m is 1.

[0082] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein alkyl is methyl or ethyl.

[0083] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein alkenyl is vinyl or1-propenyl.

[0084] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein alkynyl is 1-propynyl.

[0085] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein alkenynyl is1-pentene-4-yne.

[0086] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein alkoxy is methoxy, ethoxy,isopropoxy or cyclopropoxy.

[0087] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein aryl is phenyl or naphthyloptionally substituted with halogen.

[0088] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein arylene is phenylene.

[0089] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein halogen is chlorine.

[0090] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein perhalomethyl istrifluoromethyl.

[0091] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein heteroaryl is furan,pyrrole, pyridine, indole or benzofuran.

[0092] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein heteroarylene is furan,pyrrole, pyridine, indole or benzofuran.

[0093] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein aralkyl is benzyl.

[0094] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein aryloxy is phenoxy.

[0095] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein aralkoxy is benzyloxy.

[0096] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein n is an integer rangingfrom 1 to 3 and m is 1. In another preferred embodiment, the presentinvention is concerned with compounds of formula I wherein thesubstituents Z and Y are arranged in a trans-configuration.

[0097] In another preferred embodiment, the present invention isconcerned with compounds of formula I wherein the substituents Z and Yare arranged in a cis-configuration.

[0098] Preferred compounds of the invention are:

[0099](E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester,

[0100](E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,

[0101](Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester,

[0102](Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,

[0103](E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester,

[0104](E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid;

[0105] or a salt thereof with a pharmaceutically acceptable acid orbase, or any optical isomer or mixture of optical isomers, including aracemic mixture, or any tautomeric forms.

[0106] Also preferred compounds of the invention are:

[0107] Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,

[0108](E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,

[0109] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,

[0110](Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,

[0111] Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,

[0112](E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,

[0113] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,

[0114](Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid;

[0115] or a salt thereof with a pharmaceutically acceptable acid orbase, or any optical isomer or mixture of optical isomers, including aracemic mixture, or any tautomeric forms.

[0116] Also preferred compounds of the invention are:

[0117] Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,

[0118](E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,

[0119] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,

[0120](Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionic acid,

[0121] Ethyl(E)-(S)-2-ethoxy-3-[4-(-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,

[0122](E)-(S)-2-ethoxy-3-[4-(5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,

[0123] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,

[0124](Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid;

[0125] or a salt thereof with a pharmaceutically acceptable acid orbase, or any optical isomer or mixture of optical isomers, including aracemic mixture, or any tautomeric forms.

[0126] Also preferred compounds of the invention are:

[0127](Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester,

[0128](Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,

[0129](E)-(RS)-2-Ethoxy-3-[3-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester;

[0130] or a salt thereof with a pharmaceutically acceptable acid orbase, or any optical isomer or mixture of optical isomers, including aracemic mixture, or any tautomeric forms.

[0131] Also preferred compounds of the invention are:

[0132](E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0133](E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0134](E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0135](E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0136](E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0137](E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0138](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0139](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0140](E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0141](E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0142](E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0143](E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0144](E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0145](E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0146](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyioxy]-phenyl}-2-ethoxy-propionicacid,

[0147](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0148](E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0149](E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0150](E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0151](E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0152](E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-3-methyl-2-ethoxy-propionicacid,

[0153](E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0154](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methylpent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid,

[0155](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0156](E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0157](E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0158](E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0159](E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0160](E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0161](E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0162](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0163](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0164](E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0165](E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0166](E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0167](E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0168](E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0169](E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0170](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0171](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0172](E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0173](E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0174](E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0175](E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0176](E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0177](E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0178](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0179](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0180](E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0181](E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0182](E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0183](E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0184](E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-3-methyl-2-ethoxy-propionicacid,

[0185](E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0186](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0187](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0188](E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyi}-2-ethoxy-propionicacid,

[0189](E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0190](E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0191](E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0192](E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0193](E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0194](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0195](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyioxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0196](E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0197](E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0198](E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0199](E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0200](E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0201](E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0202](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0203](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyioxy]-3-bromo-phenyl-2-ethoxy-propionicacid,

[0204](E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyioxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0205](E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0206](E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0207](E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0208](E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0209](E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0210](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0211](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0212](E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-=ethoxy-propionicacid,

[0213](E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0214](E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0215](E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0216](E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-3-methyl-2-ethoxy-propionicacid,

[0217](E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0218](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0219](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0220](E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0221](E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0222](E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0223](E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0224](E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0225](E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0226](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0227](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0228](E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0229](E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0230](E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0231](E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0232](E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0233](E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0234](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0235](E)-(S)-3-)4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0236](E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0237](E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0238](E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0239](E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0240](E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0241](E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0242](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0243](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0244](E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0245](E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0246](E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0247](E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyioxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0248](E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-3-methyl-2-ethoxy-propionicacid,

[0249](E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl-}2-ethoxy-propionicacid,

[0250](E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0251](E)-(S)-3-{-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0252](E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0253](E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0254](E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0255](E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0256](E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0257](E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0258](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0259](E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid;

[0260] or a salt thereof with a pharmaceutically acceptable acid orbase, or any optical isomer or mixture of optical isomers, including aracemic mixture, or any tautomeric forms.

[0261] Also preferred compounds of the invention are:

[0262](Z)-(S)-3-{4-[,5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0263](Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0264](Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0265](Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0266](Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0267](Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0268](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0269](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0270](Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0271](Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid, propionic acid, ethoxy-pr op ionic acid,

[0272](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0273](Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0274](Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0275](Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-yny{oxy]-phenyl}-2-ethoxy-propionicacid,

[0276](Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0277](Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyoxy]-phenyl}-3-methyl-2-ethoxy-propionicacid,

[0278](Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0279](Z)-(S)-3-{4-[5-(1,³-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0280](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0281](Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0282](Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0283](Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0284](Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0285](Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0286](Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0287](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0288](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,

[0289](Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0290](Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0291](Z)-(S)-3-)4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0292](Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0293](Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0294](Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0295](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0296](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0297](Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0298](Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0299](Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0300](Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0301](Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0302](Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0303](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0304](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0305](Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0306](Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0307](Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0308](Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0309](Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-3-methyl-2-ethoxy-propionicacid,

[0310](Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0311](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0312](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0313](Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0314](Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chioro-phenyl}-2-ethoxy-propionicacid,

[0315](Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0316](Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0317](Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0318](Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0319](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0320](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,

[0321](Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0322](Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0323](Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0324](Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0325](Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0326](Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0327](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0328](Z)-(S)-3-{4-[5-(13,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyoxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0329](Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyi}-2-ethoxy-propionicacid,

[0330](Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0331](Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0332](Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0333](Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0334](Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0335](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0336](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0337](Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0338](Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl-2-ethoxy-propionicacid,

[0339](Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0340](Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0341](Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-3-methyl-2-ethoxy-propionicacid,

[0342](Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0343](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0344](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0345](Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0346](Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0347](Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0348](Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0349](Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0350](Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0351](Z)-(S)-3-4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0352](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,

[0353](Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0354](Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0355](Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0356](Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl-2-ethoxy-propionicacid,

[0357](Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0358](Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0359](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0360](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl-2-ethoxy-propionicacid,

[0361](Z)-(S)-3-)4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0362](Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0363](Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0364](Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0365](Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0366](Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0367](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0368](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0369](Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0370](Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl(-2-ethoxy-propionicacid,

[0371](Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0372](Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0373](Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-3-methyl-2-ethoxy-propionicacid,

[0374](Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl(-2-ethoxy-propionicacid,

[0375](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0376](Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0377](Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0378](Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyioxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0379](Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0380](Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0381](Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0382](Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0383](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,

[0384](Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid;

[0385] or a salt thereof with a pharmaceutically acceptable acid orbase, or any optical isomer or mixture of optical isomers, including aracemic mixture, or any tautomeric forms.

[0386] In the above structural formulas and throughout the presentspecification, the following terms have the indicated meaning:

[0387] The term “C₁₋₁₂-alkyl” as used herein, alone or in combination isintended to include those alkyl groups of the designated length ineither a linear or branched or cyclic configuration represents e.g.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl and the like.

[0388] Typical C₁₋₁₂-alkyl groups include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and thelike, especially preferred is methyl and ethyl.

[0389] The term “C₂₋₁₂-alkenyl” as used herein, represents anolefinically unsaturated branched or straight group having from 2 to thespecified number of carbon atoms and at least one double bond. Examplesof such groups include, but are not limited to, vinyl, 1-propenyl,2-propenyl, allyl, iso-proppenyl, 1,3-butadienyl, 1-butenyl, hexenyl,pentenyl and the like, especially preferred is vinyl and 1-propenyl.

[0390] The term “C₂₋₁₂-alkynyl” as used herein, represent an unsaturatedbranched or straight group having from 2 to the specified number ofcarbon atoms and at least one triple bond. Examples of such groupsinclude, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl and the like especially preferred is1-propynyl.

[0391] The term “C₄₋₂-alkenynyl” as used herein, represent anunsaturated branched or straight hydrocarbon group having from 4 to thespecified number of carbon atoms and both at least one double bond andat least one triple bond. Examples of such groups include, but are notlimited to, 1-penten-4-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne and thelike, especially preferred is 1-pentene-4-yne. The term “C₁₋₆-alkoxy” asused herein, alone or in combination is intended to include thoseC₁₋₆-alkyl groups of the designated length in either a linear orbranched or cyclic configuration linked thorugh an ether oxygen havingits free valence bond from the ether oxygen. Examples of linear alkoxygroups are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and thelike especially preferred is methoxy and ethoxy. Examples of branchedalkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxyand the like especially preferred is isopropoxy. Examples of cyclicalkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxyand the like, especially preferred is cyclopropoxy.

[0392] The term “C₁₋₆-alkylthio” as used herein, alone or incombination, refers to a straight or branched or cyclic monovalentsubstituent comprising a C₁₋₆-alkyl group linked through a divalentsulfur atom having its free valence bond from the sulfur atom and having1 to 6 carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio,pentylthio and the like.

[0393] Examples of cyclic alkylthio are cyclopropylthio, cyclobutylthio,cyclopentylthio, cyclohexylthio and the like.

[0394] The term “C₁₋₆-alkylamino” as used herein, alone or incombination, refers to a straight or branched or cyclic monovalentsubstituent comprising a C₁₋₆-alkyl group linked through amino having afree valence bond from the nitrogen atom e.g. methylamino, ethylamino,propylamino, butylamino, pentylamino and the like. Examples of cyclicalkylamino are cyclopropylamino, cyclobutylamino, cyclopentylamino,cyclohexylamino and the like.

[0395] The term “C₁₋₆-alkoxyC₁₋₆-alkyl” as used herein, alone or incombination, refers to a C₁₋₆-alkyl as defined herein whereto isattached a C₁₋₆-alkoxy as defined herein, e.g. methoxymethyl,ethoxymethyl, methoxyethyl, ethoxyethyl and the like.

[0396] The term “aryl” is intended to include aromatic rings, such ascarbocyclic aromatic rings selected from the group consisting of phenyl,naphthyl, (1-naphthyl or 2-naphthyl) and the like optionally substitutedwith halogen, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylesteror carboxy and the like, especially preferred is phenyl and naphtyloptionally substituted with halogen.

[0397] The term “arylene” is intended to include divalent aromaticrings, suhch as carbocyclic aromatic rings selected from the groupconsisting of phenylene, naphthylene and the like optionally substitutedwith halogen, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylesteror carboxy and the like, especially preferred is phenylene. The term“halogen” means fluorine, chlorine, bromine or iodine especiallypreferred is chlorine

[0398] The term “perhalomethyl” means trifluoromethyl, trichloromethyl,tribromomethyl or triiodomethyl, especially preferred istrifluoromethyl.

[0399] The term “C₁₋₆-dialkylamino” as used herein refers to an aminogroup wherein the two hydrogen atoms independently are substituted witha straight or branched, saturated hydrocarbon chain having the indicatednumber of carbon atoms; such as dimethylamino, N-ethyl-N-methylamino,diethylamino, dipropylamino, N-(n-butyl)-N-methylamino,di(n-pentyl)amino and the like.

[0400] The term “acyl” as used herein refers to a monovalent substituentcomprising a C₁₋₆-alkyl group linked through a carbonyl group; such ase.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and thelike.

[0401] The term “heteroaryl” as used herein, alone or in combination,refers to a monovalent substituent comprising a 5-6 membered monocyclicaromatic system or a 9-10 membered bicyclic aromatic system containingone or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.furan, thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine,pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole,oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline,quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine andthe like especially preferred is furan, pyrrole, pyridine, indole andbenzofuran.

[0402] The term “heteroarylene” as used herein, alone or in combination,refers to a divalent group comprising a 5-6 membered monocyclic aromaticsystem or a 9-10 membered bicyclic aromatic system containing one ormore heteroatoms selected from nitrogen, oxygen and sulfur, e.g. furan,thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine,pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole,thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole,benzimidazole, benzofuran, pteridine and purine and the like, especiallypreferred is furan, pyrrole, pyridine, indole and benzofuran.

[0403] The term “heteroaryloxy” as used herein, alone or in combination,refers to a heteroaryl as defined herein linked to an oxygen atom havingits free valence bond from the oxygen atom e.g. pyrrole, imidazole,pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine,isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline,isoquinoline, quinazoline, quinoxaline, indole, benzimidazole,benzofuran, pteridine and purine linked to oxygen, and the like.

[0404] The term “aralkyl” as used herein refers to a straight orbranched saturated carbon chain containing from 1 to 6 carbonssubstituted with an aromatic carbohydride; such as benzyl, phenethyl,3-phenylpropyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like,especially preferred is benzyl.

[0405] The term “aryloxy” as used herein refers to phenoxy,1-naphthyloxy, 2-naphthyloxy and the like especially preferred isphenoxy. The term “aralkoxy” as used herein refers to a C₁₋₆-alkoxygroup substituted with an aromatic carbohydride, such as benzyloxy,phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphtyl)ethoxy andthe like, especially preferred is benzyloxy.

[0406] The term “heteroaralkyl” as used herein refers to a straight orbranched saturated carbon chain containing from 1 to 6 carbonssubstituted with a heteroaryl group; such as (2-furyl)methyl,(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like.

[0407] The term “heteroaralkoxy” as used herein refers to aheteroarylalkyl as defined herein linked to an oxygen atom having itsfree valence bond from the oxygen atom, e.g. (2-furyl)methyl,(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl linked to oxygen, andthe like.

[0408] The term “arylthio” as used herein, alone or in combination,refers to an aryl group linked through a divalent sulfur atom having itsfree valence bond from the sulfur atom, the aryl group optionally beingmono- or polysubstituted with C₁₋₆-alkyl, halogen, hydroxy orC₁₋₆-alkoxy; e.g. phenylthio, (4-methylphenyl)-thio,(2-chlorophenyl)thio and the like.

[0409] As used herein, the phrase “heterocyclyl” means a monovalentsaturated or unsaturated non aromatic group being monocyclic andcontaining one or more, such as from one to four carbon atom(s), andfrom one to four N, O or S atom(s) or a combination thereof. The phrase“heterocyclyl” includes, but is not limited to, 5-membered heterocycleshaving one hetero atom (e.g. pyrrolidine, pyrroline and the like);5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions(e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane, imidazolidine,imidazoline, 4-oxazolone and the like); 5-membered heterocycles havingthree heteroatoms (e.g. tetrahydrofurazan and the like); 5-memberedheterocycles having four heteroatoms; 6-membered heterocycles with oneheteroatom (e.g. piperidine and the like); 6-membered heterocycles withtwo heteroatoms (e.g. piperazine, morpholine and the like); 6-memberedheterocycles with three heteroatoms; and 6-membered heterocycles withfour heteroatoms, and the like.

[0410] As used herein, the phrase “a divalent heterocyclic group” meansa divalent saturated or unsaturated system being monocyclic andcontaining one or more, such as from one to four carbon atom(s), and oneto four N, O or S atom(s) or a combination thereof. The phrase adivalent heterocyclic group includes, but is not limited to, 5-memberedheterocycles having one hetero atom (e.g. pyrrolidine, pyrroline and thelike); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3positions (e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane,imidazolidine, imidazoline, 4-oxazolone and the like); 5-memberedheterocycles having three heteroatoms (e.g. tetrahydrofurazan and thelike); 5-membered heterocycles having four heteroatoms; 6-memberedheterocycles with one heteroatom (e.g. piperidine and the like);6-membered heterocycles with two heteroatoms (e.g. piperazine,morpholine and the like); 6-membered heterocycles with threeheteroatoms; and 6-membered heterocycles with four heteroatoms, and thelike.

[0411] As used herein the term “treatment” includes treatment,prevention and management of such condition.

[0412] Certain of the above defined terms may occur more than once inthe above formula (I), and upon such occurrence each term shall bedefined independently of the other.

[0413] The present invention also encompasses pharmaceuticallyacceptable salts of the present compounds. Such salts includepharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable base addition salts, pharmaceutically acceptable metal salts,ammonium and alkylated ammonium salts. Acid addition salts include saltsof inorganic acids as well as organic acids. Representative examples ofsuitable inorganic acids include hydrochloric, hydrobromic, hydroiodic,phosphoric, sulfuric, nitric acids and the like. Representative examplesof suitable organic acids include formic, acetic, trichloroacetic,trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric,glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric,pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric,ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic,citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic,glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates, ketoglutarates and the like.Further examples of pharmaceutically acceptable inorganic or organicacid addition salts include the pharmaceutically acceptable salts listedin J. Pharm. Sci. 1977, 66, 2, which is incorporated herein byreference. Examples of metal salts include lithium, sodium, potassium,magnesium salts and the like. Examples of ammonium and alkylatedammonium salts include ammonium, methylammonium, dimethylammonium,trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium,butylammonium, tetramethylammonium salts and the like. Examples oforganic bases include lysine, arginine, guanidine, diethanolamine,choline and the like.

[0414] The pharmaceutically acceptable salts are prepared by reactingthe compound of formula I with 1 to 4 equivalents of a base such assodium hydroxide, sodium methoxide, sodium hydride, potassiumt-butoxide, calcium hydroxide, magnesium hydroxide and the like, insolvents like ether, THF, methanol, t-butanol, dioxane, isopropanol,ethanol etc. Mixture of solvents may be used. Organic bases like lysine,arginine, diethanolamine, choline, guandine and their derivatives etc.may also be used. Alternatively, acid addition salts wherever applicableare prepared by treatment with acids such as hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid,maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid,palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid,tartaric acid and the like in solvents like ethyl acetate, ether,alcohols, acetone, THF, dioxane etc. Mixture of solvents may also beused.

[0415] The stereoisomers of the compounds forming part of this inventionmay be prepared by using reactants in their single enantiomeric form inthe process wherever possible or by conducting the reaction in thepresence of reagents or catalysts in their single enantiomer form or byresolving the mixture of stereoisomers by conventional methods. Some ofthe preferred methods include use of microbial resolution, enzymaticresolution, resolving the diastereomeric salts formed with chiral acidssuch as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid,and the like wherever applicable or chiral bases such as brucine, (R)-or (S)phenylethylamine, cinchona alkaloids and their derivatives and thelike. Commonly used methods are compiled by Jaques et al in“Enantiomers, Racemates and Resolution” (Wiley Interscience, 1981). Morespecifically the compound of formula I may be converted to a 1:1 mixtureof diastereomeric amides by treating with chiral amines, aminoacids,aminoalcohols derived from aminoacids; conventional reaction conditionsmay be employed to convert acid into an amide; the dia-stereomers may beseparated either by fractional crystallization or chromatography and thestereoisomers of compound of formula I may be prepared by hydrolysingthe pure diastereomeric amide.

[0416] Various polymorphs of compound of general formula I forming partof this invention may be prepared by crystallization of compound offormula I under different conditions. For example, using differentsolvents commonly used or their mixtures for recrystallization;crystallizations at different temperatures; various modes of cooling,ranging from very fast to very slow cooling during crystallizations.Polymorphs may also be obtained by heating or melting the compoundfollowed by gradual or fast cooling. The presence of polymorphs may bedetermined by solid probe nmr spectroscopy, ir spectroscopy,differential scanning calorimetry, powder X-ray diffraction or suchother techniques.

[0417] The invention also encompasses prodrugs of the present compounds,which on administration undergo chemical conversion by metabolicprocesses before becoming active pharmacological substances. In general,such prodrugs will be functional derivatives of the present compounds,which are readily convertible in vivo into the required compound of theformula (I). Conventional procedures for the selection and preparationof suitable prodrug derivatives are described, for example, in “Designof Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0418] The invention also encompasses active metabolites of the presentcompounds.

[0419] Furthermore, the present compounds of formula I can be utilisedin the treatment and/or prevention of conditions mediated by nuclearreceptors, in particular the Peroxisome Proliferator-Activated Receptors(PPAR).

[0420] In a further aspect, the present invention relates to a method oftreating and/or preventing Type I or Type II diabetes.

[0421] In a still further aspect, the present invention relates to theuse of one or more compounds of the general formula I orpharmaceutically acceptable salts thereof for the preparation of amedicament for the treatment and/or prevention of Type I or Type IIdiabetes.

[0422] In a still further aspect, the present compounds are useful forthe treatment and/or prevention of IGT.

[0423] In a still further aspect, the present compounds are useful forthe treatment and/or prevention of Type 2 diabetes.

[0424] In a still further aspect, the present compounds are useful forthe delaying or prevention of the progression from IGT to Type 2diabetes.

[0425] In a still further aspect, the present compounds are useful forthe delaying or prevention of the progression from non-insulin requiringType 2 diabetes to insulin requiring Type 2 diabetes.

[0426] In another aspect, the present compounds reduce blood glucose andtriglyceride levels and are accordingly useful for the treatment and/orprevention of ailments and disorders such as diabetes and/or obesity.

[0427] In still another aspect, the present compounds are useful for thetreatment and/or prophylaxis of insulin resistance (Type 2 diabetes),impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX such as hypertension, obesity, insulin resistance, hyperglycaemia,atherosclerosis, hyperlipidemia, coronary artery disease, myocardialischemia and other cardiovascular disorders.

[0428] In still another aspect, the present compounds are effective indecreasing apoptosis in mammalian cells such as beta cells of Islets ofLangerhans.

[0429] In still another aspect, the present compounds are useful for thetreatment of certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

[0430] In still another aspect, the present compounds may also be usefulfor improving cognitive functions in dementia, treating diabeticcomplications, psoriasis, polycystic ovarian syndrome (PCOS) andprevention and treatment of bone loss, e.g. osteoporosis.

[0431] The invention also relates to pharmaceutical compositionscomprising, as an active ingredient, at least one compound of theformula I or any optical or geometric isomer or tautomeric form thereofincluding mixtures of these or a pharmaceutically acceptable saltthereof together with one or more pharmaceutically acceptable carriersor diluents.

[0432] Furthermore, the invention relates to the use of compounds of thegeneral formula I or their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts or pharmaceuticallyacceptable solvates thereof for the preparation of a pharmaceuticalcomposition for the treatment and/or prevention of conditions mediatedby nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR) such as the conditions mentionedabove.

[0433] The present invention also relates to a process for thepreparation of the above said novel compounds, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts or pharmaceutically acceptablesolvates.

[0434] The method comprises:

[0435] a)

[0436] Reacting a compound of formula II (prepared for example accordingto methods described in: Chem. Commun., 718-719, 1967; Org. Syntheses,Coll. Vol 3, 731-733, 1955; Org. Syntheses, Coll. Vol IV, 801-803, 1963.

[0437] wherein X and Y are defined as above, through a Wittig-likeprocess with for example (EtO)₂PO(CHZ)(CH₂)_(t)COOR₆ (wherein R₆ is analkyl group), in the presence of a base such as sodium hydride, EtONaand the like to give a compound of formula III

[0438] wherein X, Y, Z and R₆ are defined as above, and wherein t is0-2, and

[0439] b)

[0440] reducing a compound of formula III, wherein X, Y, Z, R₆ and t aredefined as above with a suitable reagent such as diisobutylaliminiumhydride, to give a compound of formula IV

[0441] wherein X, Y, Z and t are defined as above, and

[0442] c)

[0443] reacting a compound of formula IV, wherein X, Y, Z and t aredefined as above, with a compound of formula V

[0444] wherein Q, Ar, R₁, R₂, R₃, R₄ and m are defined as above, exceptthat m is not 0, under Mitsunobu conditions, using a reagent such astriphenylphosphine/diethylazodicarboxylate and the like to obtain acompound of formula I, wherein X, Y, Z, Q, Ar, R₁, R₂, R₃, R₄, n and mare defined as above, except that R₄ is not H, n and m are not 0, or

[0445] d)

[0446] by converting the —OH functionality in a compound of formula IV,wherein X, Y, Z and t are defined as above, to an appropriate leavinggroup (L) such as p-oluenesulfonate, methanesulfonate, halogen (forexample by methods according to: Houben-Weyl, Methoden der organischenChemie, Alkohole III, 6/1b, Thieme-Verlag 1984, 4th Ed., pp. 927-939;Comprehensive Organic Transformations. A guide to functional grouppreparations, VCH Publishers 1989, 1^(st) Ed., pp. 353-363 and J. Org.Chem., Vol. 36 (20), 3044-3045, 1971), triflate and the like, to give acompound of formula VI

[0447] wherein L, X, Y, Z and t are defined as above, or

[0448] e)

[0449] reacting a compound of formula VI

[0450] wherein L is a leaving group such as p-toluenesulfonate,methanesulfonate, halogen, triflate and the like and wherein X, Y, Z andt are defined as above with a compound of formula V

[0451] wherein Q, Ar, R₁, R₂, R₃, R₄ and m are defined as above exceptthat m is not 0, to give a compound of formula I wherein X, Y, Z, Q, Ar,R₁, R₂, R₃, R_(4,) n and m are defined as above except that R₄ is not H,n and m are not 0, or

[0452] f)

[0453] by chemical or enzymatic saponification of a compound of formulaI

[0454] wherein X, Y, Z, Q, Ar, R₁, R₂, R₃, R₄, n and m are defined asabove except that R₄ is not H, to obtain a compound of formula I,wherein X, Y, Z, Q, Ar, R., R₂, R₃, R_(4,) n and m are defined as aboveexcept that R₄ is H.

[0455] Alternative methods for the synthesis of a compound of formula I,a compound of formula III, a compound of formula IV and a compound offormula VI are:

[0456] g)

[0457] reacting a compound of formula VII

[0458] wherein X is defined as above with a compound of formula VIII

[0459] under Pd catalysed cross-coupling conditions (for example asdescribed in: Tetrahedron Lett, 39 (36), 6445-6448,1998), to give acompound of formula III wherein X, Y and R₆ are defined as above, andwherein t is 0, and Z is hydrogen.

[0460] h)

[0461] reacting a compound of formula VII with a compound of formula IX

[0462] according to a method analogous to that described in TetrahedronLett, 39 (37), 6719-6720, 1998, to give a compound of formula IIIwherein X, Y, Z and R₆ are defined as above, and wherein t is 0.

[0463] I)

[0464] Trans-cis or cis-trans isomerization of compounds I, III, IV, andVI (Arai et al., Chem. Rev., 93, pp 23-39, 1993; J. March, AdvancedOrganic Chemistry, ₄th Ed., J. Wiley & Sons, New York 1992, pp. 218,245, 745).

PHARMACOLOGICAL METHODS

[0465] In vitro PPAR Alpha and PPAR Gamma Activation Activity.

[0466] Principle

[0467] The PPAR gene transcription activation assays were based ontransient transfection into human HEK293 cells of two plasmids encodinga chimeric test protein and a reporter protein respectively. Thechimeric test protein was a fusion of the DNA binding domain (DBD) fromthe yeast GAL4 transcription factor to the ligand binding domain (LBD)of the human PPAR proteins. The PPAR LBD harbored in addition to theligand binding pocket also the native activation domain (activatingfunction 2=AF2) allowing the fusion protein to function as a PPAR liganddependent transcription factor. The GAL4 DBD will force the fusionprotein to bind only to Gal4 enhancers (of which none existed in HEK293cells). The reporter plasmid contained a Gal4 enhancer driving theexpression of the firefly luciferase protein. After transfection, HEK293cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion proteinwill in turn bind to the Gal4 enhancer controlling the luciferaseexpression, and do nothing in the absence of ligand. Upon addition tothe cells of a PPAR ligand, luciferase protein will be produced inamounts corresponding to the activation of the PPAR protein. The amountof luciferase protein is measured by light emission after addition ofthe appropriate substrate.

[0468] Methods

[0469] In vitro transactivation assays.

[0470] Cell culture and transfection: HEK293 cells were grown inDMEM+10% FCS. Cells were seeded in 96-well plates the day beforetransfection to give a confluency of 50-80% at transfection. A total of0,8 μg DNA containing 0,64 μg pM1α/γLBD, 0,1 μg pCMVβGal, 0,08 μgpGL2Gal4DBD and 0,02 μg pADVANTAGE was transfected per well using FuGenetransfection reagent according to the manufacturers instructions(Roche). Cells were allowed to express protein for 48 h followed byaddition of compound.

[0471] Plasmids:

[0472] Human PPAR a and y was obtained by PCR amplification using cDNAsynthesized by reverse transcription of mRNA from liver and adiposetissue respectively. Amplified cDNAs were cloned into pCR2.1 andsequenced. The ligand binding domain (LBD) of each PPAR isoform wasgenerated by PCR (PPARα: aa 167—C-terminus; PPARγ: aa 165—C-terminus)and fused to the DNA binding domain (DBD) of the yeast transcriptionfactor GAL4 by subcloning fragments in frame into the vector pM1generating the plasmids pM1αLBD and pM1γLBD. Ensuing fusions wereverified by sequencing. The reporter was constructed by inserting anoligonucleotide encoding five repeats of the GAL4 recognition sequence(5×CGGAGTACTGTCCTCCG(AG)) into the vector pGL2 promotor (Promega)generating the plasmid pGL2(GAL4)₅. pCMVPGal was purchased from Clontechand pADVANTAGE was purchased from Promega.

[0473] Luciferase assay:

[0474] Medium including test compound was aspirated and 100 μl PBS incl.1 mM Mg++ and Ca++ was added to each well. The luciferase assay wasperformed using the Lu-cLite kit according to the manufacturersinstructions (Packard Instruments). Light emission was quantified bycounting SPC mode on a Packard Instruments top-counter. To measureβ-galactosidase activity 25 μl supernatant from each transfection lysatewas transferred to a new microplate. β-galactosidase assays wereperformed in the microwell plates using a kit from Promega and read in amicroplate reader. The β-galactosidase data were used to normalize(transfection efficiency, cell growth etc.) the luciferase data.

[0475] Compounds:

[0476] All compounds were dissolved in DMSO and diluted 1:1000 uponaddition to the cells. Compounds were tested in quadruple in fiveconcentrations ranging form 0.01 to 30 μM. Cells were treated withcompound for 24 h followed by luciferase assay. Each compound was testedin three separate experiments. EC₅₀ values were calculated vianon-linear regression using GraphPad PRISM 3.02 (GraphPad Software, SanDiego, Calif.).The results were expressed as means. TABLE 1 In vitroPPAR alpha and PPAR gamma activation of examples according to thepresent invention. In vitro activation PPAR α PPAR γ Example no EC₅₀, μM% max^(a) EC₅₀, μM % max^(b) 6 0.20 217 0.7 108 8 0.06 139 0.31 126 120.05 195 0.34 105 18 0.16 181 2.67  91 20 0.04 154 1.42 112

[0477] Compounds were tested in at least three separate experiments infive concentrations ranging from 0.01 to 30 μM. EC₅₀'s were notcalculated for compounds producing transactivation lower than 25% at 30μM. ^(a)Fold activation relative to maximum activation obtained withWy14643 (approx. 20 fold corresponded to 100%) and with brosiglitazone(approx. 120 fold corresponded to 100%).

PHARMACEUTICAL COMPOSITIONS

[0478] In another aspect, the present invention includes within itsscope pharmaceutical compositions comprising, as an active ingredient,at least one of the compounds of the general formula I or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.

[0479] The present compounds may also be administered in combinationwith one or more further pharmacologically active substances eg.,selected from antiobesity agents, antidiabetics, antihypertensiveagents, agents for the treatment and/or prevention of complicationsresulting from or associated with diabetes and agents for the treatmentand/or prevention of complications and disorders resulting from orassociated with obesity.

[0480] Thus, in a further aspect of the invention the present compoundsmay be administered in combination with one or more antiobesity agentsor appetite regulating agents. Such agents may be selected from thegroup consisting of CART (cocaine amphetamine regulated transcript)agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4)agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF(corticotropin releasing factor) agonists, CRF BP (corticotropinreleasing factor binding protein) antagonists, urocortin agonists, P3agonists, MSH (melanocyte-stimulating hormone) agonists, MCH(melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin)agonists, serotonin re-uptake inhibitors, serotonin and noradrenalinere-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT(serotonin) agonists, bombesin agonists, galanin antagonists, growthhormone, growth hormone releasing compounds, TRH (thyreotropin releasinghormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators,leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylaseinhibitors, RXR (retinoid X receptor) modulators or TR β agonists.

[0481] In one embodiment of the invention the antiobesity agent isleptin.

[0482] In another embodiment the antiobesity agent is dexamphetamine oramphetamine.

[0483] In another embodiment the antiobesity agent is fenfluramine ordexfenfluramine.

[0484] In still another embodiment the antiobesity agent is sibutramine.

[0485] In a further embodiment the antiobesity agent is orlistat.

[0486] In another embodiment the antiobesity agent is mazindol orphentermine.

[0487] Suitable antidiabetics comprise insulin, GLP-1 (glucagon likepeptide-1) derivatives such as those disclosed in WO 98/08871 to NovoNordisk A/S, which is incorporated herein by reference as well as orallyactive hypoglycaemic agents.

[0488] The orally active hypoglycaemic agents preferably comprisesulphonylureas, biguanides, meglitinides, glucosidase inhibitors,glucagon antagonists such as those disclosed in WO 99/01423 to NovoNordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassiumchannel openers such as those disclosed in WO 97/26265 and WO 99/03861to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV(dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, compounds modifying the lipid metabolism suchas antihyperlipidemic agents and antilipidemic agents as HMG CoAinhibitors (statins), compounds lowering food intake, RXR agonists andagents acting on the ATP-dependent potassium channel of the ,-cells.

[0489] In one embodiment of the invention the present compounds areadministered in combination with insulin.

[0490] In a further embodiment the present compounds are administered incombination with a sulphonylurea eg. tolbutamide, glibenclamide,glipizide or glicazide.

[0491] In another embodiment the present compounds are administered incombination with a biguanide eg. mefformin.

[0492] In yet another embodiment the present compounds are administeredin combination with a meglitinide eg. repaglinide or senaglinide.

[0493] In a further embodiment the present compounds are administered incombination with an α-glucosidase inhibitor eg. miglitol or acarbose.

[0494] In another embodiment the present compounds are administered incombination with an agent acting on the ATP-dependent potassium channelof the P-cells eg. tolbutamide, glibenclamide, glipizide, glicazide orrepaglinide.

[0495] Furthermore, the present compounds may be administered incombination with nateglinide.

[0496] In still another embodiment the present compounds areadministered in combination with an antihyperlipidemic agent orantilipidemic agent eg. cholestyramine, colestipol, clofibrate,gemfibrozil, lovastatin, pravastatin, simvastatin, probucol ordextrothyroxine.

[0497] In a further embodiment the present compounds are administered incombination with more than one of the above-mentioned compounds eg. incombination with a sulphonylurea and mefformin, a sulphonylurea andacarbose, repaglinide and mefformin, insulin and a sulphonylurea,insulin and mefformin, insulin, insulin and lovastatin, etc.Furthermore, the present compounds may be administered in combinationwith one or more antihypertensive agents. Examples of antihypertensiveagents are P-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, quinapril and ramipril, calcium channel blockers such asnifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazemand verapamil, and a-blockers such as doxazosin, urapidil, prazosin andterazosin. Further reference can be made to Remington: The Science andPractice of Pharmacy, 19^(th) Edition, Gennaro, Ed., Mack PublishingCo., Easton, Pa., 1995.

[0498] It should be understood that any suitable combination of thecompounds according to the invention with one or more of theabove-mentioned compounds and optionally one or more furtherpharmacologically active substances are considered to be within thescope of the present invention.

[0499] Pharmaceutical compositions containing a compound of the presentinvention may be prepared by conventional techniques, e.g. as describedin Remington: The Science and Practise of Pharmacy, 19^(th) Ed., 1995.The compositions may appear in conventional forms, for example capsules,tablets, aerosols, solutions, suspensions or topical applications.

[0500] Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent may include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax. The formulations may also include wetting agents,emulsifying and suspending agents, preserving agents, sweetening agentsor flavouring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

[0501] The pharmaceutical compositions can be sterilized and mixed, ifdesired, with auxiliary agents, emulsifiers, salt for influencingosmotic pressure, buffers and/or colouring substances and the like,which do not deleteriously react with the active compounds.

[0502] The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral e.g.rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,intranasal, ophthalmic solution or an ointment, the oral route beingpreferred.

[0503] If a solid carrier is used for oral administration, thepreparation may be tabletted, placed in a hard gelatin capsule in powderor pellet form or it can be in the form of a troche or lozenge. If aliquid carrier is used, the preparation may be in the form of a syrup,emulsion, soft gelatin capsule or sterile injectable liquid such as anaqueous or non-aqueous liquid suspension or solution.

[0504] For nasal administration, the preparation may contain a compoundof formula I dissolved or suspended in a liquid carrier, in particularan aqueous carrier, for aerosol application. The carrier may containadditives such as solubilizing agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

[0505] For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil. Tablets, dragees, orcapsules having talc and/or a carbohydrate carrier or binder or the likeare particularly suitable for oral application. Preferable carriers fortablets, dragees, or capsules include lactose, corn starch, and/orpotato starch. A syrup or elixir can be used in cases where a sweetenedvehicle can be employed.

[0506] A typical tablet which may be prepared by conventional tablettingtechniques may contain: Core: Active compound (as free compound or saltthereof) 5 mg Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose,microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mgMagnesium stearate Ad. Coating: HPMC approx. 9 mg *Mywacett 9-40 Tapprox. 0.9 mg

[0507] The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of diseases related to the regulation ofblood sugar.

[0508] Such mammals include also animals, both domestic animals, e.g.household pets, and non-domestic animals such as wildlife.

[0509] The compounds of the invention are effective over a wide dosagerange. For example, in the treatment of adult humans, dosages from about0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per daymay be used. A most preferable dosage is about 0.1 mg to about 70 mg perday. In choosing a regimen for patients it may frequently be necessaryto begin with a dosage of from about 2 to about 70 mg per day and whenthe condition is under control to reduce the dosage as low as from about0.1 to about 10 mg per day. The exact dosage will depend upon the modeof administration, on the therapy desired, form in which administered,the subject to be treated and the body weight of the subject to betreated, and the preference and experience of the physician orveterinarian in charge.

[0510] Generally, the compounds of the present invention are dispensedin unit dosage form comprising from about 0.1 to about 100 mg of activeingredient together with a pharmaceutically acceptable carrier per unitdosage.

[0511] Usually, dosage forms suitable for oral, nasal, pulmonary ortransdermal administration comprise from about 0.001 mg to about 100 mg,preferably from about 0.01 mg to about 50 mg of the compounds of formulaI admixed with a pharmaceutically acceptable carrier or diluent.

[0512] Any novel feature or combination of features described herein isconsidered essential to this invention.

EXAMPLES

[0513] The process for preparing compounds of formula I, andpreparations containing them, is further illustrated in the followingexamples, which however, are not to be construed as limiting.

[0514] The structures of the compounds are confirmed by either elementalanalysis (MA) nuclear magnetic resonance (NMR), mass spectrometry (MS)or optical rotation. NMR shifts (δ) are given in parts per million (ppm)and only selected peaks are given. mp is melting point and is given in °C. Column chromatography was carried out using the technique describedby W. C. Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silicagel 60 (Art 9385). The optical rotation was measured on a Advanced LaserPolarimeter.

[0515] Compounds used as starting materials are either known compoundsor compounds which can readily be prepared by methods known per se.Abbrevations: THF: tetrahydrofuran DMSO: dimethylsulfoxide MTBE:tertbutylmethylether CDCl₃: deutorated chloroform DMF:N,N-dimethylformamide min: minutes h: hours

Example 1

[0516]

[0517](E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid Ethyl Ester

[0518] Method 1

[0519] a)

[0520] A solution of triethyl phosphonoacetate (25.8 g, 115 mmol) intoluene (100 mL) was added at 0° C. to a stirred suspension of sodiumhydride (60% in oil, 3.12 g, 130 mmol) in toluene (300 mL) and themixture stirred at OOC for 30 min. A solution of 3-phenylpropargylaldehyde (Org. Syntheses, Coll. Vol 3, 731-733, 1955) (10.0 g, 77 mmol)in dry THF (15 mL) was added, the mixture slowly warmed to roomtemperature, and stirring continued for 16 h. The reaction mixture wasquenched with ethanol (25 mL) and water (300 mL), the organic phaseseparated, and the aqueous phase extracted with dichloromethane (300mL). The combined organic phases were concentrated in vacuo, andsubmitted to flash column chromatography, petroleum ether/toluene (1:1)graduated to petroleum ether/toluene (1:9) as eluent, to give (1.21 g,8%) of (E)-5-phenyl-pent-2-en-4-ynoic acid ethyl ester.

[0521]¹H NMR (CDCl₃, 300 MHz) δ: 1.30 (t, 3H), 4.25 (q, 2H), 6.30 (d,1H, J_(trans)=15 Hz), 6.98 (d, 1H, J_(trans)=15 Hz), 7.30-7.40 (m, 3H),7.45-7.50 (m, 2H).

[0522] b)

[0523] Diisobutylaluminium hydride (1.0 M solution in toluene, 42 mL, 42mmol) was added, under a nitrogen atmosphere at −70° C., to a stirredsolution of (E)-5-phenyl-pent-2-en-4-ynoic acid ethyl ester (1.2 g, 5.99mmol) in dry THF (105 mL). After stirring for 1.5 h, the reactionmixture was quenched with methanol (5 mL) followed by saturated aqueousRochelle's salt (90 mL) and 1 N sodium hydroxide (40 mL). The organicphase was separated, and the aqueous phase extracted with ethyl acetate(250 mL, 2x). The combined organic phases were dried (MgSO₄), filteredand concentrated in vacuo to give 948 mg (100%) of(E)-5-phenyl-pent-2-en-4-yn-1-ol.

[0524]¹H NMR (CDCl₃, 300 MHz) δ: 2.20 (bs, 1H), 4.25 (d, 2H), 5.95 (dt,1H, Jtrans=15 Hz), 6.35 (dt, 1H, J_(trans)=15 Hz), 7.23-7.35 (m, 3H),7.35-7.48 (m, 2H).

[0525] c)

[0526] (E)-5-Phenyl-pent-2-en-4-yn-1-ol (328 mg, 2.07 mmol),tributylphosphine (606 mg, 3.0 mmol) and(S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester(Tetrahedron Letters, Vol. 35, No. 19, 3139-3142, 1994) (495 mg, 2.07mmol) were successively dissolved in dry benzene (30 mL) under anitrogen atmosphere and the solution cooled to 0° C. Solid1,1′-(azodicarbonyl) dipiperidine (756 mg, 3.0 mmol) was added, themixture stirred for 10 min., then warmed to room temperature and stirredfor 16 h. The reaction mixture was filtered and the filtrateconcentrated in vacuo. The product was purified by flash columnchromatography eluting with toluene graduated to toluene/ethyl acetate(19:1) to give 450 mg (57%) of the title compound.

[0527]¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.25 (t, 3H), 2.95 (d,2H), 3.30-3.42 (m, 1H), 3.55-3.67 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H),4.60 (d, 2H), 6.15 (dt, 1H, J_(trans)=15 Hz), 6.48 (dt, 1H, J_(trans)=15Hz), 6.85 (d, 2H), 7.15 (d, 2H), 7.28-7.35 (m, 3H), 7.40-7.46 (m, 2H).

[0528] [α]₆₇₀ ²⁵=30°±4°.

[0529] Method 2

[0530] a)

[0531] To a mixture of (E)-5-phenyl-pent-2-en-4-yn-1-ol (Method lb) (4.9g, 31.0 mmol) and triethylamine (3.8 g, 38.0 mmol) in drydichloromethane (200 mL) was added methanesulfonyl chloride (3.8 g, 33mmol) dropwise. Stirring was continued at room temperature overnight.The reaction mixture was concentrated in vacuo and the residue washedwith heptane/dichloromethane (×2) to give 4.5 g (82%) crude(E)-(5-chloro-pent-3-en-1-ynyl)-benzene.

[0532]¹H NMR (CDCl₃, 300 MHz) δ: 4.13 (d, 2H)), 6.0 (d, 1H, J_(trans)=15Hz), 6.29 (dt, 1H, J_(trans)=15 Hz), 7.28-7.35 (m, 3H), 7.40-7.48 (m,2H).

[0533] b)

[0534] To a solution of (E)-(5-chloro-pent-3-en-1-ynyl)-benzene (177 mg,1.0 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethylester (238 mg, 1.0 mmol) in acetone (15 mL) was added potassiumcarbonate (700 mg, 5.0 mmol) and potassium iodide (17 mg, 0.1 mmol). Themixture was heated to reflux over night with stirring. Water was addedand the product extracted with tert-butyl methyl ether (×3) The combinedorganic phases were dried (MgSO₄), filtered and concentrated in vacuo,to give the title compound as a crude product.

[0535] Method 3

[0536] a)

[0537] A solution of (E)-5-phenyl-pent-2-en-4-yn-1-ol (Method 1b) (980mg, 6.2 mmol) in dry toluene (20 mL) was cooled on ice and phosphorustribromide (0.59 mL, 6.2 mmol) added slowly. After 16 h at 5° C. themixture was diluted with ethyl acetate and washed with water (×3). Theorganic phase was concentrated in vacuo and the residue extracted withheptane (×3). The combined heptane phases were concentrated in vacuo togive 900 mg of crude (E)-(5-bromo-pent-3-en-1-ynyl)-benzene. (Accordingto NMR the product contained -5% of the (Z)-isomer).

[0538]¹H NMR (CDCl₃, 300 MHz) δ: 4.02 (d, 1H), 4.25 (d, 0.05H), 5.82 (d,0.05H, J_(cis)=8 Hz), 5.95 (d, 1H, J_(trans)=16 Hz), 6.18 (dt, 0.05H,J_(cis)=8 Hz), 6.35 (dt, 1H, J_(trans)=16 Hz), 7.26-7.35 (m, 3H),7.35-7.48 (m, 2H).

Example 2

[0539]

[0540](E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0541] Aqueous sodium hydroxide (1N, 5 mL, 5.0 mmol) was added to astirred solution of(E)-(S)-2-ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester (example 1) (450 mg, 1.18 mmol) in ethanol (5 mL) andthe resulting mixture stirred at room temperature for 16 h. The ethanolwas evaporated in vacuo and the mixture acidified to pH 1 with 1Nhydrochloric acid. The product was extracted into ethyl acetate (30mL×2), and the combined organic phases dried (MgSO₄), filtered andevaporated to give 225 mg (54%) of the title compound as white crystals.

[0542]¹H NMR (CDCl₃, 300 MHz) δ: 1.20 (t, 3H), 2.97 (dd,1H), 3.10 (dd,1H), 3.42-3.65 (m, 2H), 4.05 (dd,1H), 4.63 (dd, 2H), 6.08 (dt, 1H,J_(trans)=15 Hz), 6.39 (dt, 1H, J_(trans)=15 Hz), 6.85 (d, 2H), 7.15 (d,2H), 7.30-7.35 (m, 3H), 7.40-7.48 (m, 2H).

[0543] [α]₆₇₀ ²⁵=23°±3°.

Example 3

[0544]

[0545](Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid Ethyl Ester

[0546] 1,1′-(azodicarbonyl) dipiperidine (0.504 g, 2.0 mmol) was addedat 0° C. to a stirred solution of tributylphosphine (0.493 mL, 2.0mmol), (Z)-3-methyl-5-phenyl-pent-2-en-4-yn-1-ol (0.172 g, 1.0 mmol) (J.Org. Chem. 1999, 64 (21), 7687-7692), and (S)-ethyl2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.262 g, 1.1 mmol) in drybenzene (20 mL), the mixture allowed to warm to room temperature, andstirring continued for 24 h. The resulting mixture was evaporated invacuo, and the residue purified by flash column chromatography on silicagel (20% ethyl acetate in n-heptane eluent) to give(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester as an oil; 0.267 g (68%).

[0547]¹H NMR (300 MHz, CDCl₃) δ: 1.1-1.25 (6H, m), 2.0 (3H, d), 2.93(2H, d), 3.25-3.38 (1H, m), 3.51-3.62 (1H, m), 3.97 (1H, t), 4.13 (2H,q), 4.80 (2H, dd), 5.95 (1H, dt), 6.86 (2H, d), 7.15 (2H, d), 7.25-7.35(3H, m), 7.40-7.43 (2H, m).

Example 4

[0548]

[0549](Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0550] Sodium hydroxide (1N, 1.25 mL, 1.25 mmol) was added to a solutionof(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester (example 3) (0.246 g, 0.627 mmol) in ethanol (20 mL)and the mixture stirred at 70° C. for 2.5 h. After cooling to roomtemperature the resulting mixture was partitioned between water (50 mL)and ethyl acetate (50 mL). The aqueous phase was collected, acidifiedwith 1 N hydrochloric acid (5 mL) and extracted into ethyl acetate (100mL). The organic phase was washed with brine, dried (Na₂SO₄) andevaporated to give (E)-(S)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionic acid as an oil; 0.150 g (66%).

[0551]¹H NMR (300 MHz, CDCl₃) δ: 1.05 (3H, t), 1.92 (3H, d), 2.8 (1H,dd), 2.92 (1H, dd), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.9 (1H, dd), 4.7(2H, dd), 5.85 (1H, dt), 6.8 (2H, d), 7.1 (2H, d), 7.2-7.25 (3H, m),7.3-7.4 (2H, m), 8.9 (1H, br s).

Example 5

[0552]

[0553](E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid Ethyl Ester

[0554] The title compound was prepared from of(E)-3-methyl-5-phenyl-pent-2-en-4-yn-1-ol (0.172 g, 1.0 mmol), (J. Med.Chem. 1998, 41(14), 2524-2536), tributylphosphine (0.370 mL, 1.5 mmol),1,1′-(azodicarbonyl) dipiperidine (0.378 g, 1.5 mmol) and (S)-ethyl2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.262 g, 1.1 mmol) in drybenzene (20 mL) by a procedure analogous to that described in example 3,yielding 0.276 g (68%) of(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester.

[0555]¹H NMR (300 MHz, CDCl₃) δ: 1.1-1.25 (6H, m), 1.98 (3H, d), 2.95(2H, d), 3.29-3.4 (1H, m), 3.53-3.65 (1H, m), 3.95 (1H, t), 4.15 (2H,q), 4.60 (2H, dd), 6.15 (1H, dt), 6.8 (2H, d), 7.15 (2H, d), 7.20-7.3(3H, m), 7.35-7.45 (2H, m).

Example 6

[0556]

[0557](E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0558] The title compound was prepared from(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester (example 5) (0.270 g, 0.698 mmol ) and sodium hydroxide(1N, 1.4 mL, 1.4 mmol) by a procedure analogous to that described inexample 4 yielding 0.100 g (39%) of(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid.

[0559]¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 1.98 (3H, d), 2.9 (1H,dd), 2.05 (1H, dd), 3.4-3.5 (1H, m), 3.55-3.65 (1H, m), 4.05 (1H, dd),4.62 (2H, dd), 6.15 (1H, m), 6.8 (2H, d), 7.15 (2H, d), 7.3 (3H, m),7.43 (2H, m).

Example 7

[0560]

[0561] Ethyl(E)-(S)-2-ethoxy-3-[-4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate

[0562] Method 1

[0563] a)

[0564] To a solution of 1,3-dichloro-5-iodo-benzene (3.44 g, 12.6 mmol)in THF (220 mL) was added PdCl₂(PPh₃)₂ (904 mg, 1.29 mmol),3-butyn-2-one (2.18 g, 32.0 mmol), copper(I)iodide (380 mg, 2 mmol) anddiisopropylamine (44 mL). The reaction mixture was stirred at roomtemperature for 48 hours, filtered and evaporated. The residue waspurified by column chromatography using methylene chloride:hexanes (1:1)as eluent. The desired 4-(3,5-dichloro-phenyl)-3-butyn-2-one product wasisolated in 977 mg yield.

[0565]¹H NMR (300 MHz, CDCl₃) δ: 2.46 (s, 3H), 7.45 (s, 3H).

[0566] b)

[0567] To a solution of sodium (163 mg, 6.8 mmol) in ethanol (6 mL) at−10° C. was added triethyl phosphonoacetate (1.37 mL, 6.8 mmol) and thereaction mixture was stirred for 5 minutes. A solution of4-(3,5-dichloro-phenyl)-3-butyn-2-one (214 mg, 5.7 mmol) in ethanol (4mL) was added and the reaction mixture stirred overnight at roomtemperature and evaporated. The residue was treated with water (10 mL)and extracted with 3×30 mL ethyl acetate. The dried organic phases wereevaporated to give a mixture of (E)- and(Z)-3-methyl-5-(3,5-dichlorophenyl)-pent-2-en-4-ynoic acid ethyl esters.The mixture was separated by column chromatography usinghexanes:methylene chloride (10:1) as eluent, giving pure (E) in 130 mg,and pure (Z) in 160 mg yields.

[0568] (E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethylester: ¹H NMR (300 MHz, CDCl₃) δ: 1.29 (t, 3H), 2.36 (s, 3H), 4.20 (q,2H), 6.16 (m, 1H), 7.34 (s, 3H).

[0569] (Z)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethylester: ¹H NMR (300 MHz, CDCl₃) δ: 1.29 (t, 3H), 2.12 (s, 3H), 2.25 (q,2H), 6.09 (m, 1H), 7.34 (m, 1H), 7.40 (m, 2H).

[0570] c)

[0571] To a solution of(E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester(130 mg, 0.46 mmol) in THF (0.5 mL) was added dropwisediisobutylaluminium hydride (1.0 M solution in toluene, 2.1 mL, 2.1mmol) at −20° C. The reaction mixture was stirred for 2 hours at −20°C., whereafter saturated ammonium chloride was added. The mixture wastreated with ethyl acetate and decalite and filtered. The filtrate wasevaporated to give crude(E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol in 113 mgyield.

[0572]¹H NMR (300 MHz, CDCl₃) 3: 1.85 (s, 3H), 2.00 (br.s, 1H), 4.20 (d,2H), 6.04 (m, 1H), 7.20 (s, 3H).

[0573] d)

[0574] To a solution of(E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol (113 mg, 0.46mmol) in THF (10 mL) was added triphenylphosphine (218 mg, 0.71 mmol) at0° C. To the mixture was added diethyl azodicarboxylate (0.109 mL, 0.71mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester(169 mg, 0.71 mmol) and the reaction mixture was stirred at 0° C. for 2h and then at room temperature overnight. Water (15 mL) was added andthe mixture was extracted with methylene chloride (3×30 mL). Thecombined and dried organic phases were evaporated and the residuepurified by column chromatography using methylene chloride as eluent togive the title compound in 35 mg yield.

[0575]¹H NMR (300 MHz, CDCl₃) δ:1.16 (t, 3H), 1.23 (t, 3H), 1.98 (s,3H), 2.97 (d, 2H), 3.42-3.30 (m, 1H), 3.65-3.55 (m, 1H), 3.97 (t, 1H),4.16 (q, 2H), 4.62 (d, 2H), 6.20 (m, 1H), 8.83 (d, 2H), 7.16 (d, 2H),7.37 (m, 3H).

[0576] Method 2

[0577] a)

[0578] A solution of 1-bromo-3,5-dichloro-benzene (904 mg, 4.0 mmol),PdCl₂(PPh₃)₂ (96 mg, 0.08 mmol), 2-methyl-3-butyn-2-ol (672 mg, 8.0mmol) and Cul (4 mg, 0.02 mmol) in diethylamine (16 mL) was stirred atroom temperature for 50 h. The reaction mixture was evaporated and theresidue purified by column chromatography using methylene chloride aseluent. The desired product 3-(2,5-dichlorophenyl}-2-methyl-3-butyn-2-olwas isolated in 910 mg (99%) yield.

[0579]¹H NMR (300 MHz, CDCl₃) δ: 1.62 (6H, s), 7.30 (3H, s).

[0580] b)

[0581] To a solution of 3-(2,5-dichlorophenyl}-2-methyl-3-butyn-2-ol(840 mg, 3.46 mmol) in dry toluene (15 mL) was added sodium hydroxidepellets (45 mg) at room temperature. The reaction mixture was heated anda mixture of toluene and formed acetone was distilled of. The reactionmixture was washed with aqueous potassium carbonate (1 M, 2.5 mL), water(2.5 mL) and brine (2.5 mL). The organic phase was dried and evaporatedto give the desired =product 1,3-dichloro-phenyl acetylene in 537 mg(91%) yield. ¹H NMR (300 MHz, CDCl₃) δ: 3.15 (1H, s), 7.37 (3H, s). .=c) To a solution of 1,3-dichloro-phenyl acetylene (6.07 g, 35.5 mmol)in dry THF (60 mL) was added palladium acetate (186 mg, 0.68 mmol),ethyl 2-butynoate (5.97 g, 53.2 mmol) and tris(2,6-dimethoxyphenyl)phosphine (316 mg, 0.68 mmol) at room temperature.The reaction mixture was stirred for 18 h and filtered. The filtrate waswashed with water (10 mL), and the water phase was extracted with ether(10 mL). The combined organic phases were dried and evaporated. Theresidue was purified by column chromatography using heptane:THF (20:1)as eluent. (E)-3-Methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acidethyl ester was isolated in 4.65 g (46%) yield.

[0582] d)

[0583] The title compound was prepared from(E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl esteraccording to the procedure described in method 1,c-d.

Example 8

[0584]

[0585](E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0586] Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionatewas hydrolysed as described in Example 2 to give the title compound.

[0587]¹H NMR (300 MHz, CDCl₃) δ: 1.12 (t, 3H), 1.95 (s, 3H), 3.12-2.85(m, 2H), 3.48-3.32 (m, 1H), 3.65-3.53 (m,1H), 4.03 (m, 1H), 4.59 (d,2H), 6.17 (t, 1H), 6.80 (d, 2H), 7.15 (d, 2H), 7.30 (s, 3H).

Example 9

[0588]

[0589] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate

[0590] a)

[0591] (Z)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol was madefrom (Z)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethylester (160 mg) (example 7b) using the conditions described in example7c. Yield 140 mg.

[0592]¹H NMR (300 MHz, CDCl₃) δ: 1.88 (s, 3H), 1.92 (br. s, 1H), 4.33(d, 2H), 5.90 (t, 1H), 7.21 (s, 3H).

[0593] b)

[0594] The title compound was prepared from(Z)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol (140 mg) usingthe conditions described in example 7d. Yield 172 mg.

[0595]¹H NMR (300 MHz, CDCl₃) δ: 1.17 (t, 3H), 1.25 (t, 3H), 2.00 (s,3H), 2.95 (d, 2H), 3.42-3.28 (m, 1H), 3.67-3.55 (m, 1H), 3.98 (t, 1H),4.16 (q, 2H), 4.77 (d, 2H), 6.02 (t, 1H), 6.86 (d, 2H), 7.28 (d, 2H),7.32 (s, 3H).

Example 10

[0596]

[0597](Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0598] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionatewas hydrolysed as described in Example 2 to give the title compound.Yield 164 mg.

[0599]¹H NMR (300 MHz, CDCl₃) δ: 1.18 (t, 3H), 2.01 (s, 3H), 3.10-2.90(m, 2H), 3.46-3.33 (m, 1H), 3.67-3.55 (m, 1H), 4.04 (m, 1H), 4.75 (d,2H), 6.02 (t, 1H), 6.87 (d, 2H), 7.18 (d, 2H), 7.33 (s, 3H).

Example 11

[0600]

[0601] Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate

[0602] The title compound was made as described in example 7a-d using3-trifluoromethyl-1-iodo-benzene instead of 1,3-dichloro-5-iodo-benzenein example 7a.

[0603]¹H NMR (300 MHz, CDCl₃) δ: 1.18 (t, 3H), 1.24 (t, 3H), 2.00 (s,3H), 2.96 (d, 2H), 3.42-3.31 (m, 1H), 3.66-3.55 (m, 1H), 3.98 (t, 1H),4.27 (q, 2H), 4.65 (d, 2H), 6.23 (1H), 6.84 (d, 2H), 7.18 (d, 2H),7.71-7.38 (m, 5H).

Example 12

[0604]

[0605](E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0606] Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionatewas hydrolysed as described in Example 2 to give the title compound.

[0607]¹H NMR (300 MHz, CDCl₃) δ: 1.19 (t, 3H), 1.98 (s, 3H), 3.12-2.90(m, 2H), 3.48-3.36 (m, 1H), 3.69-3.56 (m, 1H), 4.50 (m, 1H), 4.64 (d,2H), 6.21 (t, 1H), 6.85 (d, 2H), 7.18 (d, 2H), 7.70-7.49 (m, 5H).

Example 13

[0608]

[0609] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate

[0610] The title compound was synthesised from(Z)-3-methyl-5-(3-trifluromethyl-phenyl)-pent-2-en-4-yn-1-ol which wasderived from the reaction sequence described in example 11 using theconditions described in example 7c-d.

[0611]¹H NMR (300 MHz, CDCl₃) δ: 1.18 (t, 3H), 2.23 (t, 3H), 2.03 (s,3H), 2.96 (d, 2H), 3.42-3.30 (m, 1H), 3.66-3.55 (m, 1H), 3.96 (t, 1H),4.15 (q, 2H), 4.82 (d, 2H), 6.03 (t, 1H), 6.87 (d, 2H), 7.17 (d, 2H),7.70-7.43 (m, 5H).

Example 14

[0612]

[0613](Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0614] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionatewas hydrolysed as described in Example 2 to give the title compound.

[0615]¹H NMR (300 MHz, CDCl₃) δ: 1.16 (t, 3H), 2.02 (s, 3H), 3.10-2.92(m, 2H), 3.47-3.36 (m, 1H), 3.68-3.57 (m, 1H), 4.03 (m, 1H), 4.80 (d,2H), 6.02 (t, 1H), 6.89 (d, 2H), 7.18 (d, 2H), 7.72-7.42 (m, 5H).

Example 15

[0616]

[0617] Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate

[0618] The title compound was made as described in example 7a-d using1-iodonaphthalene instead of 1,3-dichloro-5-iodo-benzene in example 7a.

[0619]¹H NMR (300 MHz, CDCl₃) δ:1.18 (t, 3H), 1.24 (t, 3H), 2.08 (s,3H), 2.96 (d, 2H), 3.42-3.30 (m, 1H), 3.66-3.53 (m, 1H), 3.98 (t, 1H),4.15 (q, 2H), 4.65 (d, 2H), 6.30 (m, 1H), 6.86 (d, 2H), 7.18 (d, 2H),7.86-7.38 (m, 6H), 8.33 (d, 1H).

Example 16

[0620]

[0621](E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0622] Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionatewas hydrolysed as described in Example 2 to give the title compound.

[0623]¹H NMR (300 MHz, CDCl₃) δ: 1.19 (t, 3H), 1.98 (s, 3H), 3.12-2.90(m, 2H), 3.48-3.36 (m, 1H), 3.69-3.56 (m, 1H), 4.05 (m, 1H), 4.66 (d,2H), 6.30 (t, 1H), 6.85 (d, 2H), 7.18 (d, 2H), 7.90-7.45 (m, 6H), 8.44(d, 1H).

Example 17

[0624]

[0625] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate

[0626] The title compound was synthesised from(Z)-3-methyl-5-(1-naphthyl)-pent-2-en-4-yn-1-ol isolated in example 15using the conditions described in example 7c-d.

[0627]¹H NMR (300 MHz, CDCl₃) δ: 1.18 (t, 3H), 1.23 (t, 3H), 2.14 (s,3H), 2.97 (d, 2H), 3.42-3.30 (m, 1H), 3.66-3.53 (m, 1H), 3.98 (t, 1H),4.15 (q, 2H), 4.95 (d, 2H), 6.06 (m, 1H), 6.94 (d, 2H), 7.18 (d, 2H),7.86-7.40 (m, 6H), 8.30 (m, 1H).

Example 18

[0628]

[0629] (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(l-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionic Acid

[0630] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionatewas hydrolysed as described in Example 2 to give the title compound.

[0631]¹H NMR (300 MHz, CDCl₃) δ: 1.04 (t, 3H), 2.02 (s, 3H), 3.00-2.80(m, 2H), 3.34-3.22 (m, 1H), 3.57-3.46 (m, 1H), 3.94 (m, 1H), 4.83 (d,2H), 5.94 (t, 1H), 6.84 (d, 2H), 7.08 (d, 2H), 7.75-7.26 (m, 6H), 8.20(m, 1H), 9.2 (br.s, 1H).

Example 19

[0632]

[0633] Ethyl(E)-(S)-2-ethoxy-3-[4-(-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate

[0634] a)

[0635] To a solution of 1,3-dichloro-5-iodo-benzene (5.44 g, 20 mmol) indiethylamine (75 mL) was added PdCl₂(PPh₃)₂ (280 mg, 0.4 mmol),trimethylsilylacetylene (2.36 g, 24.0 mmol) and copper(I)iodide (20 mg,0.1 mmol). The reaction mixture was stirred at room temperature for 24h, filtered and evaporated. The residue was purified by columnchromatography using heptane:ethyl acetate (8:2) as eluent. The desired(3,5-dichloro-phenylethynyl)-trimethylsilane product was isolated in4.85 g yield.

[0636]¹H NMR (300 MHz, CDCl₃) δ: 0.09 (s, 9H), 7.15 (m, 3H).

[0637] b)

[0638] To a solution of (3,5-dichloro-phenylethynyl)-trimethylsilane(4.85 g, 19.9 mmol) in methanol (50 mL) was added 1 M potassiumhydroxide (30 mL). The reaction mixture was stirred 1 h at roomtemperature and evaporated. The residue was treated with water (10 mL)and extracted with 3×40 mL diethyl ether. The tried organic phases wereevaporated to give the desired 1,3-dichloro-5-ethynyl-benzene product in2.3 g yield.

[0639]¹H NMR (300 MHz, CDCl₃) δ: 2.13 (s, 1H), 7.38 (s, 3H).

[0640] c)

[0641] To a solution of 1,3-dichloro-5-ethynyl-benzene (1.52 g, 8.9mmol) in triethylamine (32.4 mL) was added PdCl₂(PPh₃)₂ (57.15 mg, 0.08mmol), (E)-3-iodo-prop-2-enoic-acid ethyl ester (1.84 g, 8.1 mmol) andcopper(l)iodide (7.7 mg, 0.04 mmol). The reaction mixture was stirredfor 2 h at 50° C., whereafter the reaction mixture was cooled to roomtemperature, water (30 mL) added and the mixture extracted with diethylether (3×20 mL). The combined and dried organic phases were evaporatedto give crude (E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethylester in 1.1 g yield.

[0642]¹H NMR (300 MHz, CDCl₃) δ: 1.32 (t, 3H), 4.22 (q, 2H), 6.32 (d,1H, J=16 Hz), 6.92 (d, 1H, J=16 Hz), 7.37 (s, 3H).

[0643] d)

[0644] To a solution of diisobutylaluminium hydride (1.0 M solution intoluene, 20 mL, 20 mmol) at-78° C. was slowly added(E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester (1.1 g,4.08 mmol). The reaction mixture was stirred for 2 h at −78° C., whereafter the reaction mixture was poured into hydrocloride acid (6N, 50 mL) and extracted with diethyl ether (3×40 mL) The combined and driedorganic phases were evaporated to give crude(E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol in 750 mg yield.

[0645]¹H NMR (300 MHz, CDCl₃) δ: 4.3 (dd, 2H), 5.95 (dt, 1H, J=5 and 16Hz), 6.4 (dt, 1H, J=5 and 16 Hz), 7.30 (s, 3H).

[0646] e)

[0647] The title compound was prepared from(E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol (454 mg, 2 mmol) usingthe conditions described in example 7d. Yield 125 mg yield.

[0648]¹H NMR (300 MHz, CDCl₃) δ: 1.14 (t, 3H), 1.22 (t, 3H), 2.95 (d,2H), 3.30-3.42 (m, 1H), 3.55-3.67 (m, 1H), 3.95 (t, 1H), 4.16 (q, 2H),4.6 (dd, 2H, J=1.5 and 5 Hz), 6.05 (dt, 1H, J=1.5and 16 Hz), 6.35 (dt,1H, J=5and 16 Hz), 6.83 (d, 2H), 7.15 (d, 2H), 7.36 (m, 3H).

Example 20

[0649]

[0650](E)-(S)-2-Ethoxy-3-[4-(5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0651] Ethyl(E)-(S)-2-ethoxy-3-[4-(5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionatewas hydrolysed as described in Example 2 to give the title compound.

[0652]¹H NMR (300 MHz, CDCl₃) δ: 1.19 (t, 3H), 2.88-3.12 (m, 2H),3.37-3.50 (m, 1H), 3.65-3.70 (m, 1H), 4.05 (m, 1H), 4.70 (dd, 2H, J=1.5and 5 Hz), 6.1 (dt, 1H, J=1.5 and 16 Hz), 6.45 (dt, 1H, J=5and 16 Hz),6.85 (d, 2H), 7.18 (d, 2H), 7.30 (s, 3H).

Example 21

[0653]

[0654] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate

[0655] a)

[0656] (Z)-5-(3,5-Dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl esterwas made from cis-3-iodo acrylic acid ethyl ester (Can J Chem, 72 (8),1816-1819, 1994). (4 g) using the conditions described in example 19 c.Yield 4.62 g.

[0657]¹H NMR (300 MHz, CDCl₃) δ: 1.4 (t, 3H), 4.3 (q, 2H), 6.2 (d, 1H,J=11 Hz), 6.34 (d, 1H, J=11 Hz), 7.32 (s, 1H) 7.4 (s, 2H).

[0658] b)

[0659] (Z)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1l-ol was made from(Z)-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester (4.6 g)using the conditions described in example 19 d. Yield 3.63 g.

[0660]¹H NMR (300 MHz, CDCl₃) δ: 4.4 (dd, 2H, J=1.5 and 6.5 Hz), 5.75(dt, 1H, J=1.5 and 11 Hz), 6.21 (dt, 1H, J=6.5 and 11 Hz), 7.3 (s, 3H).

[0661] c)

[0662] The title compound was from(Z)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol (300 mg, 1.32 mmol)using the conditions described in example 19 e. Yield 180 mg yield.

[0663]¹H NMR (300 MHz, CDCl₃) δ: 1.12 (t, 3H), 1.2 (t, 3H), 2.9 (d, 2H),3.26-3.44 (m, 1H), 3.51-3.69 (m, 1H), 3.94 (t, 1H), 4.14 (q, 2H), 4.85(dd, 2H, J=1.8 and 6.3 Hz), 5.87 (dt, 1H, J=1.8 and 11 Hz), 6.25 (dt,1H, J=6.3 and 11 Hz), 6.82 (d, 2H), 7.15 (d, 2H), 7.33 (m, 3H).

Example 22

[0664]

[0665](Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicAcid

[0666] Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionatewas hydrolysed as described in Example 2 to give the title compound.Yield 100 mg.

[0667]¹H NMR (300 MHz, DMSO-D₆) δ: 1.16 (t, 3H), 2.85-3.05 (m, 2H),3.3-3.45 (m, 1H), 3.6-3.7 (m, 1H), 4.06 (m, 1H), 4.9 (dd, 2H, J=1.8 and6.2 Hz), 6.1 (dt, 1H, J=1.8 and 11 Hz), 6.45 (dt, 1H, J=6.2 and 11 Hz),6.93 (d, 2H), 7.20 (d, 2H), 7.65 (d, 2H), 7.71 (d, 1H).

Example 23

[0668]

[0669](Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester

[0670] a)

[0671] (Z)-5-phenyl-pent-2-en-4-ynoic acid ethyl ester was made fromcis-3-iodo acrylic acid ethyl ester (2 g) and phenylacetylene using theconditions described in example 19 c. Yield 1.24 g.

[0672]¹H NMR (300 MHz, CDCl₃) δ: 1.3 (t, 3H), 4.25 (q, 2H), 6.12 (d, 1H,J_(cis)=11.3 Hz), 6.35 (d, 1H, J_(cis)=11.3 Hz), 7.36 (m, 3H) 7.53 (m,2H).

[0673] b)

[0674] (Z)-5-phenyl-pent-2-en-4-yn-1-ol was made from(Z)-5-phenyl-pent-2-en-4-ynoic acid ethyl ester (1.0 g) using theconditions described in example 19 d. Yield 0.7 g.

[0675]¹H NMR (300 MHz, CDCl₃) δ: 4.5 (dd, 2H, J=1.5 and 6.5 Hz), 5.80(dt, 1H, J=1.5 and 10.5 Hz), 6.14 (dt, 1H, J=6.4 and 10.5 Hz), 7.31 (m,3H), 7.43 (m, 2H).

[0676] c)

[0677] The title compound was prepared from(Z)-5-phenyl-pent-2-en-4-yn-1-ol (200 mg, 1.3 mmol) using the conditionsdescribed in example 19 e. Yield 380 mg.

[0678]¹H NMR (300 MHz, CDCl₃) δ: 1.2 (dt, 6H), 2.98 (d, 2H), 3.3-3.41(m, 1H), 3.53-3.68 (m, 1H), 3.95 (t, 1H), 4.18 (q, 2H), 4.9 (dd, 2H,J=1.6 and 6.4 Hz), 5.95 (dt, 1H, J=1.6 and 11 Hz), 6.2 (dt, 1H, J=6.4and 11 Hz), 6.89 (d, 2H), 7.17 (d, 2H), 7.35 (m, 3H) ), 7.47 (m, 2H).

Example 24

[0679]

[0680](Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid

[0681] Ethyl(Z)-(S)-2-ethoxy-3-[4-(phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionatewas hydrolysed as described in Example 2 to give the title compound.Yield 264 mg. ¹H NMR (300 MHz, DMSO-D₆) δ: 1.15 (t, 3H), 2.8-3.0 (m,2H), 3.3-3.4 (m, 1H), 3.5-3.65 (m, 1H), 3.96 (m, 1H), 4.89 (dd, 2H,J=1.6 and 6.3 Hz), 6.08 (dt, 1H, J=1.6 and 11 Hz), 6.3 (dt, 1H, J=6.3and 11 Hz), 6.9 (d, 2H), 7.20 (d, 2H), 7.4 (m, 3H), 7.5 (m, 2H).

Example 25

[0682]

[0683](E)-(RS)-2-Ethoxy-3-[3-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester

[0684] a)

[0685] NaH 60% in paraffin oil (1.18g, 29.5 mmol) was added to asolution of diethoxy-phosphoryl-ethoxy-ethylacetate (7.46g, 27.8 mmol))in dry THF (40 mL) at 0° C. 3-Benzyloxybenzaldehyde (ALDRICH) (5.0 g,23.6 mmol) dissolved in dry THF (20 mL) was added dropwise keeping thetemperature below 10° C. The reaction mixture was allowed to reach roomtemperature followed by the addition of water. The product was extractedinto MTBE, and the combined organic phases dried (Na₂SO₄), filtered andevaporated to give 7.6 g (99%) of(E,Z)-3-(3-benzyloxyphenyl}-2-ethoxyacrylic acid ethyl ester as a yellowoil.

[0686]¹H NMR (CDCl₃, 400 MHz) δ: 1.09 (t), 1.34 (t), 1.37 (t), 3.92 (q),3.98 (q), 4.12 (q), 4.30 (q), 5.04 (s), 5.09 (s), 6.95 (s), 7.26 (s),7.2-7.5 (m).

[0687] b)

[0688] (E,Z)-3-(3-Benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester (6.8g) dissolved in ethyl acetate (40 mL) was hydrogenated at 10 bar usingPd/C (10%) (1.08 g) until the reaction was shown to be completed byHPLC. The reaction mixture was filtered through a pad of celite and thesolvent evaporated. The product was purified by column chromatographyeluting with ethyl acetate/heptane 1:2 to give 3.1 g (62%) of(R,S)-2-ethoxy-3-hydroxyphenyl)propanoic acid ethyl ester.

[0689]¹H NMR (CDCl₃, 400 MHz) δ: 1.16 (t, 3H), 1.23 (t, 3H), 2.97-2.95(m, 2H), 3.41-3.33 (dq, 1H), 3.65-3.57 (dq, 1H), 4.02(t, 1H), 4.17 (q,2H), 5.33 (s, 1H), 6.81-6.70 (m, 3H), 7.15 (t, 1H). ¹³C-NMR (75 MHz,CDCl₃) 614.51, 15.36, 39,58, 61,48, 66,74, 80.52, 114.15, 116.87,121.79, 129.81, 139.07, 156.20, 173.27. MS m/z (MH⁺) 239.2. Elementalanalysis: Anal. Calcd. for C₁₃H₁₈O₄: C, 65.53;H, 7.61%. Found: C,65.98;H, 7.96.

[0690] c)

[0691] The title compound (120 mg, 63%) was prepared from(R,S)-2-ethoxy-3-(3-hydroxyphenyl)propanoic acid ethyl ester (120 mg,0.5 mmol) and (E)-5-phenyl-pent-2-en-4-yn-1-ol (example 1, method 1b)(79 mg, 0.5 mmol), by a procedure analogous to that described inexample 1 (method 1c).

1. A compound of formula (I)

wherein X is hydrogen or X is C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl,aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl each of whichis optionally substituted with one or more substituents selected fromhalogen, perhalomethyl, hydroxy, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,hydroxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio, acyl,aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy,heteroaralkoxy, C₁₋₆-alkylthio, cyano, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, carboxy or C₁₋₆-alkylester; and Y is hydrogen or Y isC₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl, aryl,heteroaryl, aralkyl or heteroaralkyl each of which is optionallysubstituted with one or more substituents selected from halogen,C₁₋₆-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy orC₁₋₆-alkylester; and Z is hydrogen, halogen, hydroxy or Z is C₁₋₆-alkylor C₁₋₆-alkoxy each of which is optionally substituted with one or moresubstituents selected from C₁₋₆-alkoxy, halogen, hydroxy, carboxy, aminoor cyano; and Q is O, S or NR₅, wherein R₅ is hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aralkyl or heteroaralkyl andwherein R₅ is optionally substituted with one or more substituentsselected from halogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and Ar isarylene, heteroarylene or a divalent heterocyclic group each of whichcan be optionally substituted with one or more substituents selectedfrom C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can be optionallysubstituted with halogen, hydroxy, carboxy or C₁₋₆-alkylester; and R₁ ishydrogen, hydroxy or halogen; or R₁ forms a bond together with R₂; andR₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together with R₁; andR₃ is hydrogen, C₁₋₆-alkyl, C₂₋₄-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl,aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl, heterocyclyl, heteroaryl orheteroaralkyl groups optionally substituted with one or moresubstituents selected from halogen, perhalomethyl, hydroxy, cyano,carboxy or C₁₋₆alkylester; and R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₄-alkynyl, C₄₋₆-alkenynyl or aryl; n is an integer ranging from 0 to3; and m is an integer ranging from 0 to 1; or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvatethereof, or any tautomeric forms, stereoisomers, mixture ofstereoisomers including a racemic mixture, or polymorphs.
 2. A compoundaccording to claim 1 of formula (I)

wherein X is hydrogen or X is C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl,aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl each of whichis optionally substituted with one or more substituents selected fromhalogen, perhalomethyl, hydroxy, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,hydroxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio, acyl,aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy,heteroaralkoxy, C₁₋₆-alkylthio, cyano, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, carboxy or C₁₋₆-alkylester; and Y is hydrogen or Y isC₁₋₂-alkyl, C₂₋₁alkenyl, C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl, aryl,heteroaryl, aralkyl or heteroaralkyl each of which is optionallysubstituted with one or more substituents selected from halogen,C₁₋₆-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy orC₁₋₆-alkylester; and Z is hydrogen, halogen, hydroxy or Z is C₁₋₆-alkylor C₁₋₆-alkoxy each of which is optionally substituted with one or moresubstituents selected from C₁₋₆-alkoxy, halogen, hydroxy, carboxy, aminoor cyano; and Q is O, S or NR₅, wherein R₅ is hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aralkyl or heteroaralkyl andwherein R₅ is optionally substituted with one or more substituentsselected from halogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and Ar isarylene, heteroarylene or a divalent heterocyclic group each of whichcan be optionally substituted with one or more substituents selectedfrom C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can be optionallysubstituted with halogen, hydroxy, carboxy or C₁₋₆-alkylester; and R₁ ishydrogen, hydroxy or halogen; or R₁ forms a bond together with R₂; andR₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together with R₁; andR₃ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl,aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl, heterocyclyl, heteroaryl orheteroaralkyl groups optionally substituted with one or moresubstituents selected from halogen, perhalomethyl, hydroxy, cyano,carboxy or C₁₋₆alkylester; and R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₄-alkenyl,C₂₋₆-alkynyl, C₄₋₆-alkenynyl or aryl; n is an integer ranging from 1 to3; and m is 1; or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers including a racemic mixture, orpolymorphs.
 3. A compound according to any one of the preceding claimsof formula (I)

wherein X is hydrogen, C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl or heterocyclyl optionallysubstituted with one or more substituents selected from halogen,perhalomethyl, hydroxy, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy,C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl,aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy,C₁₋₆-alkylthio, cyano, amino, C₁₋₆-alkylamino, C₁₋₆dialkylamino, carboxyor C₁₋₆-alkylester; and Y is hydrogen, C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl,C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl, aryl, heteroaryl, aralkyl orheteroaralkyl optionally substituted with one or more substituentsselected from halogen, C₁₋₆-alkyl, perhalomethyl, hydroxy, aryl,heteroaryl, amino, carboxy or C₁₋₆-alkylester; and Z is hydrogen,halogen, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy optionally substituted withone or more substituents selected from C₁₋₆-alkoxy, halogen, hydroxy,carboxy, amino or cyano; and Q is O, S or NR₅, wherein R₅ is hydrogen,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆alkynyl, C₄₋₆alkenynyl, aralkyl orheteroaralkyl and wherein R₅ is optionally substituted with one or moresubstituents selected from halogen, hydroxy, C₁₋₆-alkoxy, amino orcarboxy; and Ar is arylene, heteroarylene or a divalent heterocyclicgroup each of which can be optionally substituted with one or moresubstituents selected from C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of whichcan be optionally substituted with halogen, hydroxy, carboxy orC₁₋₆-alkylester; and R₁ is hydrogen, hydroxy or halogen; or R₁ forms abond together with R₂; and R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms abond together with R₁; and R₃ is hydrogen, C₁₋₆-alkyl, C₂₋₄-alkenyl,C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl,acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionallysubstituted with one or more substituents selected from halogen,perhalomethyl, hydroxy, cyano, carboxy or C₁₋₆-alkylester; and R₄ ishydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl oraryl; n is an integer ranging from 0 to 3; and m is an integer rangingfrom 0 to 1; or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers including a racemic mixture, orpolymorphs.
 4. A compound according to any one of the preceding claimswherein X is aryl, heteroaryl or heterocyclyl optionally substitutedwith one or more substituents selected from halogen, perhalomethyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy,heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
 5. Acompound according to any one of the preceding claims wherein X is aryl,heteroaryl or heterocyclyl each of which is optionally substituted withone or more substituents selected from halogen, perhalomethyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy,heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
 6. Acompound according to any one of the preceding claims wherein X is aryloptionally substituted with one or more substituents selected fromhalogen, perhalomethyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy,arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy orheteroaralkoxy.
 7. A compound according to any one of the precedingclaims wherein X is phenyl or naphthyl each of which is optionallysubstituted with one or more substituents selected from halogen orperhalomethyl.
 8. A compound according to any one of the precedingclaims wherein X is phenyl optionally substituted with one or moresubstituents selected from halogen.
 9. A compound according to any oneof the preceding claims wherein X is phenyl.
 10. A compound according toany one of the preceding claims wherein X is heteroaryl optionallysubstituted with one or more substituents selected from halogen,perhalomethyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryloxy, arylthio,aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy orheteroaralkoxy.
 11. A compound according to any one of the precedingclaims wherein X is heterocyclyl optionally substituted with one or moresubstituents selected from halogen, perhalomethyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl,heteroaralkyl, heteroaryloxy or heteroaralkoxy.
 12. A compound accordingto any one of the preceding claims wherein Y is hydrogen, C₁₋₁₂-alkyl oraryl.
 13. A compound according to any one of the preceding claimswherein Y is hydrogen or methyl.
 14. A compound according to any one ofthe preceding claims wherein Y is hydrogen.
 15. A compound according toany one of the preceding claims wherein Z is hydrogen or C₁₋₆-alkoxy.16. A compound according to any one of the preceding claims wherein Z ishydrogen.
 17. A compound according to any one of the preceding claimswherein Q is O.
 18. A compound according to any one of the precedingclaims wherein Ar is arylene optionally substituted with one or moresubstituents selected from C₁₋₆-alkyl or C₁₋₆-alkoxy each of which canbe optionally substituted with carboxy.
 19. A compound according to anyone of the preceding claims wherein Ar is phenylene.
 20. A compoundaccording to any one of the preceding claims wherein R₁ is hydrogen orR₁ forms a bond together with R₂.
 21. A compound according to any one ofthe preceding claims wherein R₁ is hydrogen.
 22. A compound according toany one of the preceding claims wherein R₂ is hydrogen or R₂ forms abond together with R₁.
 23. A compound according to any one of thepreceding claims wherein R₂ is hydrogen.
 24. A compound according to anyone of the preceding claims wherein R₃ is C₁₋₆-alkyl.
 25. A compoundaccording to any one of the preceding claims wherein R₃ is C₁₂-alkyl.26. A compound according to any one of the preceding claims wherein R₄is hydrogen.
 27. A compound according to any one of the preceding claimswherein n is
 1. 28. A compound according to any one of the precedingclaims wherein m is
 1. 29. A compound according to any one of thepreceding claims wherein alkyl is methyl or ethyl.
 30. A compoundaccording to any one of the preceding claims wherein alkenyl is vinyl or1-propenyl.
 31. A compound according to any one of the preceding claimswherein alkynyl is 1-propynyl.
 32. A compound according to any one ofthe preceding claims wherein alkenynyl is 1-pentene-4-yne.
 33. Acompound according to any one of the preceding claims wherein alkoxy ismethoxy, ethoxy, isopropoxy or cyclopropoxy.
 34. A compound according toany one of the preceding claims wherein aryl is phenyl or naphthyloptionally substituted with halogen.
 35. A compound according to any oneof the preceding claims wherein arylene is phenylene.
 36. A compoundaccording to any one of the preceding claims wherein halogen ischlorine.
 37. A compound according to any one of the preceding claimswherein perhalomethyl is trifluoromethyl.
 38. A compound according toany one of the preceding claims wherein heteroaryl is furan, pyrrole,pyridine, indole or benzofuran.
 39. A compound according to any one ofthe preceding claims wherein heteroarylene is furan, pyrrole, pyridine,indole or benzofuran.
 40. A compound according to any one of thepreceding claims wherein aralkyl is benzyl.
 41. A compound according toany one of the preceding claims wherein aryloxy is phenoxy.
 42. Acompound according to any one of the preceding claims wherein aralkoxyis benzyloxy.
 43. A compound according to any one of the precedingclaims wherein n is an integer ranging from 1 to 3 and m is
 1. 44. Acompound according to any of the preceding claims wherein thesubstituents Z and Y are arranged in a trans-configuration.
 45. Acompound according to any of the preceding claims wherein thesubstituents Z and Y are arranged in a cis-configuration.
 46. Thecompound according to claim 1 , 2 or 3 which is(E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester,(E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,(Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester,(Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,(E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester,(E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid; or a pharmaceutically acceptable salt thereof.
 47. The compoundaccording to claim 1 , 2 or 3 which is Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid, Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid, Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid, Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid; or a pharmaceutically acceptable salt thereof.
 48. The compoundaccording to claim 1 , 2 or 3 which is Ethyl(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(l-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid, Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid, Ethyl(E)-(S)-2-ethoxy-3-[4-(-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,(acid, Ethyl(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate,(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionicacid; or a pharmaceutically acceptable salt thereof.
 49. The compoundaccording to claim 1 , 2 or 3 which is(Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester,(Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid,(E)-(RS)-2-Ethoxy-3-[3-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionicacid ethyl ester; or a pharmaceutically acceptable salt thereof.
 50. Thecompound according to claim 1 , 2 or 3 which is(E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl(-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyi}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-(4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxyl-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-3-methyl-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methylpent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid,(E)-(S)-3-{-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyoxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-(4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-3-methyl-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyi}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-(4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-3-methyl-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-3-methyl-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyioxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(E)-(S)-3-{4-(5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid; or a pharmaceutically acceptable salt thereof.
 51. The compoundaccording to claim 1 , 2 or 3 which is(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyi}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxyl-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-3-methyl-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methylpent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-choro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyioxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-)5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-3-methyl-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid, ethoxy-propionic acid,(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyioxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-3-methyl-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-{2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-3-methyl-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-(4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid,(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionicacid; or a pharmaceutically acceptable salt thereof.
 52. Apharmaceutical composition comprising, as an active ingredient, acompound according to any one of the preceding compound claims or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.
 53. A compositionaccording to claim 52 in unit dosage form, comprising from about 0.05 toabout 100 mg, preferably from about 0.1 to about 50 mg of the compoundaccording to any one of the preceding compound claims or apharmaceutically acceptable salt thereof.
 54. A pharmaceuticalcomposition useful in the treatment and/or prevention of conditionsmediated by nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR), the composition comprising, asan active ingredient, a compound according to any one of the precedingcompound claims or a pharmaceutically acceptable salt thereof togetherwith a pharmaceutically acceptable carrier or diluent.
 55. Apharmaceutical composition useful in the treatment and/or prevention ofdiabetes and/or obesity, the composition comprising, as an activeingredient, a compound according to any one of the preceding compoundclaims or a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.
 56. A pharmaceuticalcomposition according to any one of the claims 52-55 for oral, nasal,transdermal, pulmonal, or parenteral administration.
 57. A method forthe treatment of ailments, the method comprising administering to asubject in need thereof an effective amount of a compound according toany one of the preceding compound claims or a pharmaceuticallyacceptable salt thereof, or of a composition according to any one of thepreceding claims 52-56.
 58. A method for the treatment and/or preventionof conditions mediated by nuclear receptors, in particular thePeroxisome Proliferator-Activated Receptors (PPAR), the methodcomprising administering to a subject in need thereof an effectiveamount of a compound according to any one of the preceding compoundclaims or a pharmaceutically acceptable salt thereof, or of acomposition according to any one of the preceding claims 52-56.
 59. Amethod for the treatment and/or prevention of diabetes and/or obesity,the method comprising administering to a subject in need thereof aneffective amount of a compound according to any one of the precedingcompound claims or a pharmaceutically acceptable salt thereof, or of acomposition according to any one of the preceding claims 52-56.
 60. Themethod according to claim 57 , 58 or 59 wherein the effective amount ofthe compound according to any one of the preceding compound claims or apharmaceutically acceptable salt or ester thereof is in the range offrom about 0.05 to about 100 mg per day, preferably from about 0.1 toabout 50 mg per day.
 61. Use of a compound according to any one of thepreceding compound claims or a pharmaceutically acceptable salt thereoffor the preparation of a medicament.
 62. Use of a compound according toany one of the preceding compound claims or a pharmaceuticallyacceptable salt thereof for the preparation of a medicament useful inthe treatment and/or prevention of conditions mediated by nuclearreceptors, in particular the Peroxisome Proliferator-Activated Receptors(PPAR).
 63. Use of a compound according to any one of the precedingcompound claims or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for treatment and/or prevention of diabetesand/or obesity.
 64. A process for the preparation of a compound offormula (I) which comprises reacting a compound of formula IV

wherein X, Y, Z are as defined in claim 1 and t is 0-2 with a compoundof formula V

wherein Q, Ar, R₁, R₂, R₃, R₄ and m are as defined in claim 1 , exceptthat m is not 0, under Mitsunobu conditions, using a reagent such astriphenylphosphine/diethylazodicarboxylate and the like to obtain acompound of formula I, wherein X, Y, Z, Q, Ar, R₁, R₂, R₃, R₄, n and mare as defined in claim 1 , except that R₄ is not H and n and m are not0.
 65. The process according to claim 64 wherein tributylphosphine and1,1′-(azodicarbonyl) dipiperidine are used as coupling reagent andwherein either dry benzene or dry THF are used as solvent.
 66. A processfor the preparation of a compound of formula (I) which comprises: a)converting the —OH functionality in a compound of formula IV

wherein X, Y, Z and t are as defined in claim 64 to an appropriateleaving group (L) such as p-toluenesulfonate, methanesulfonate, halogen,triflate and the like, to give a compound of formula VI

wherein X, Y, Z and t are as defined in claim 64 and L is a leavinggroup such as p-toluenesulfonate, methanesulfonate, halogen, triflateand the like, and b) reacting a compound of formula VI

wherein X, Y, Z and t are as defined in claim 64 and wherein L is aleaving group such as p-toluenesulfonate, methanesulfonate, halogen,triflate and the like with a compound of formula V

wherein Q, Ar, R₁, R₂, R₃, R₄ and m are as defined in claim 1 , exceptthat m is not 0, to give a compound of formula I wherein X, Y, Z, Q, Ar,R₁, R₂, R₃, R₄, n and m are as defined in claim 1 except that R₄ is notH and n and m are not
 0. 67. The process as in claim 66 wherein L ischlorine and wherein the reagent used in step a) are triethyl amine, drydichloromethane and methanesulfonylchloride.
 68. The process as in claim66 wherein L is chlorine and wherein the reagent used in step b) ispotassium carbonate, and sodium- or potassium iodide and wherein thesolvent is acetone and wherein the reaction temperature is reflux.
 69. Apharmaceutical composition suitable for treating type I diabetes, typeII diabetes, impaired glucose tolerance, insulin resistance or obesitycomprising a compound according to any of the claims 1 to 51 or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, or any tautomeric forms, stereoisomers,mixture of stereoisomers including a racemic mixture, or polymorphstogether with one or more pharmaceutically acceptable carriers ordiluents and an ACE (angiotensin converting enzyme) inhibitor.
 70. Theuse of a compound according to any one of the claims 1 to 51 or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, or any tautomeric forms, stereoisomers,mixture of stereoisomers including a racemic mixture, or polymorphstogether with one or more pharmaceutically acceptable carriers ordiluents and an ACE (angiotensin converting enzyme) inhibitor for thepreparation of a medicament suitable for the treatment of type Idiabetes, type II diabetes, impaired glucose tolerance, insulinresistance or obesity.
 71. A method of treating type I diabetes, type IIdiabetes, impaired glucose tolerance, insulin resistance or obesitycomprising administering to a subject in need thereof an effectiveamount of a compound according to any of the claims 1 to 51 or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, or any tautomeric forms, stereoisomers,mixture of stereoisomers including a racemic mixture, or polymorphstogether with one or more pharmaceutically acceptable carriers ordiluents and an ACE (angiotensin converting enzyme) inhibitor to saidsubject.
 72. A pharmaceutical composition suitable for treating type Idiabetes, type II diabetes, impaired glucose tolerance, insulinresistance or obesity comprising a compound according to any of theclaims 1 to 51 or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers including a racemic mixture, orpolymorphs together with one or more pharmaceutically acceptablecarriers or diluents and an agent stimulating insulin release from gcells such as a meglitinide, like repaglinide or senaglinide.
 73. Theuse of a compound according to any one of the claims 1 to 51 or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, or any tautomeric forms, stereoisomers,mixture of stereoisomers including a racemic mixture, or polymorphstogether with one or more pharmaceutically acceptable carriers ordiluents and an agent stimulating insulin release from P cells such as ameglitinide, like repaglinide or senaglinide, for the preparation of amedicament suitable for the treatment of type I diabetes, type IIdiabetes, impaired glucose tolerance, insulin resistance or obesity. 74.A method of treating type I diabetes, type II diabetes, impaired glucosetolerance, insulin resistance or obesity comprising administering to asubject in need thereof an effective amount of a compound according toany of the claims 1 to 51 and an agent stimulating insulin release from,cells such as a meglitinide, like repaglinide or senaglinide, to saidsubject.
 75. A pharmaceutical composition suitable for treating type Idiabetes, type II diabetes, impaired glucose tolerance, insulinresistance or obesity comprising a compound according to any of theclaims 1 to 51 or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers including a racemic mixture, orpolymorphs together with one or more pharmaceutically acceptablecarriers or diluents and a biguanide like mefformin.
 76. The use of acompound according to any one of the claims 1 to 51 or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, or any tautomeric forms, stereoisomers,mixture of stereoisomers including a racemic mixture, or polymorphstogether with one or more pharmaceutically acceptable carriers ordiluents and a biguanide, like metformin, for the preparation of amedicament suitable for the treatment of type I diabetes, type IIdiabetes, impaired glucose tolerance, insulin resistance or obesity. 77.A method of treating type I diabetes, type II diabetes, impaired glucosetolerance, insulin resistance or obesity comprising administering to asubject in need thereof an effective amount of a compound according toany of the claims 1 to 51 or a pharmaceutically acceptable salt thereof,or a pharmaceutically acceptable solvate thereof, or any tautomericforms, stereoisomers, mixture of stereoisomers including a racemicmixture, or polymorphs together with one or more pharmaceuticallyacceptable carriers or diluents and a biguanide, like metformin, to saidsubject.
 78. A pharmaceutical composition suitable for treating type Idiabetes, type II diabetes, impaired glucose tolerance, insulinresistance or obesity comprising a compound according to any of theclaims 1 to 51 or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers including a racemic mixture, orpolymorphs together with one or more pharmaceutically acceptablecarriers or diluents and a HMG CoA inhibitor.
 79. The use of a compoundaccording to any one of the claims 1 to 51 or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvatethereof, or any tautomeric forms, stereoisomers, mixture ofstereoisomers including a racemic mixture, or polymorphs together withone or more pharmaceutically acceptable carriers or diluents and a HMGCoA inhibitor for the preparation of a medicament suitable for thetreatment of type I diabetes, type II diabetes, impaired glucosetolerance, insulin resistance or obesity.
 80. A method of treating typeI diabetes, type II diabetes, impaired glucose tolerance, insulinresistance or obesity comprising administering to a subject in needthereof an effective amount of a compound according to any of the claims1 to 51 or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers including a racemic mixture, orpolymorphs together with one or more pharmaceutically acceptablecarriers or diluents and a HMG CoA inhibitor to said subject.